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1
Cattaneo, Dario. "Therapeutic drug monitoring of novel immunosuppressants." Thesis, Open University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424822.
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Therapeutic drug monitoring is primarily undertaken for narrow therapeutic inde:drugs, such as immunosuppressants. These drugs have reduced the incidence of acute rejection and improved allograft survival. However, due to their narrow therapeutic index, small variations in blood levels may result in inadequate levels of immunosuppression or toxic drug concentrations. To overcome these problems individual dose regimen based-on phannacokinetic monitoring has been proposed in the past years. Indeed, several studies have previously documented a significant association between cyclosporine whole blood levels and patient's clinical outcome, expressed as rejection episodes as well as drug-related adverse events. Novel immunosuppressive agents have been recently introduced on the market (such as rapamycins and mycophenolic acid-releasing formulations). However, data on their phannacokinetics, which in tum could be useful for the definition of therapeutic ranges, are scanty. To address this issue we have used a chromatographic method for the measurement of mycophenolic acid levels in kidney transplant recipients. Although this immunosuppressant is usually given in a fixed daily dose regimen, we found a positive correlation between drug levels, but not dose, and renal function. As additional analysis, significant phannacokinetic interactions between mycophenolic acid and concomitant immunosuppressive regimens have been identified. Similarly, novel chromatographic methods for the analysis of rapamycins in the whole blood have been developed in our laboratory, and applied to identify phannacokinetic interactions between these anJ other inununosuppressive agents. In the last part of my research project. I have also presented preliminary data on the application of pharmacogenetics analysis in patients given cyclosporine as part of their immunosuppressive regimenIn conclusion, it can be reasonably speculated that TDM based on pharmacokinetic. as well as novel pharmacogenetic approaches, can be considered as reliable tools to guide drug dosing in organ transplantation setting, ultimately resulting in a significant improvement of long term graft and patient survival
2
Reynolds, Helen Elizabeth. "Therapeutic drug monitoring of the antiretrovirals." Thesis, University of Liverpool, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273036.
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Caffarel-Salvador, E. "Hydrogel-formimg microneedles for therapeutic drug monitoring." Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669672.
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Therapeutic drug monitoring (TOM) focuses on measurement of drugs with narrow therapeutic windows. Inappropriate concentrations of these drugs can elicit either an absence of therapeutic response or toxic effects. Microneedles (MN) have previously been studied for their ability to painlessly penetrate the stratum corneum, allowing transdermal delivery of various compounds. Interest in MN technology to sample analytes is increasing due to their minimally-invasive characteristics when compared to conventional needles. . . To overcome problems associated with the use of conventional needles, this study aimed to identify the most suitable polymeric MN array design and utilise this, for the first time, as a sampling device capable of imbibing large amounts of fluid for TOM. Hydrogel-forming MN arrays were fabricated from blends of poly(methyl vinyl ether-eo-maleic acid) crosslinked with poly(ethylene glycol) both with and without pore-forming agents. These MN were used in combination with reverse iontophoresis and hygroscopic Iyophilised tablets to further enhance fluid uptake by polymeric matrices. Theophylline, a bronchodilator with a narrow therapeutic window, was chosen as the model drug of the study. A high-performance liquid chromatography (HPLC) method was developed and validated for detection of theophylline. This study proved the capacity of hydrogel-forming MN to take up theophylline, in vitro and in vivo, and release it in water solution for HPLC quantification. Theophylline was successfully detected and quantified from 12 of 24 MN after 1 h insertion in the back of rats dosed with 10 mg theophylline/kg body mass. While this study posed certain challenges, including problems optimising HPLC methodology and difficulties designing a method to extract theophylline in vivo, the potential of MN as a novel in vivo TOM technology with significant clinical potential was proven. Ideally, given the findings of this study, future work will focus on the use of hydrogel-forming MN for TOM in human volunteers.
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Vogel, Brooke. "Therapeutic Drug Monitoring of Apixaban Using Chromogenic Kits." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/honors/560.
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Apixaban is a novel oral anticoagulant that prevents clotting by directly inhibiting Factor Xa in the coagulation cascade. Due to its different pharmacokinetics, previous standards for testing anticoagulant concentrations are ineffective at measuring apixaban. In this study, Hyphen Biomed Biophen Direct Xa Inhibitor and Biophen Heparin chromogenic kits from Aniara Diagnostica were used along with a NanoDrop™ One/OneC Microvolume UV-Vis Spectrophotometer to see if either of these kits provide acceptable precision and accuracy for the quantification of apixaban in plasma samples, as well as if there is a significant difference in these two kits at varying concentrations of apixaban.
Apixaban is a novel oral anticoagulant that prevents clotting by directly inhibiting Factor Xa in the coagulation cascade. Due to its different pharmacokinetics, previous standards for testing anticoagulant concentrations are ineffective at measuring apixaban. In this study, Hyphen Biomed Biophen Direct Xa Inhibitor and Biophen Heparin chromogenic kits from Aniara Diagnostica were used along withused witha NanoDrop™ One/OneC Microvolume UV-Vis Spectrophotometer to see if either of these kits provide acceptable precision and accuracy for the quantification of apixaban in plasma samples,as well as and to evaluate if there is a significant difference in these two kits at varying concentrations of apixaban.
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PELLIZZONI, ELENA. "Molecularly imprinted polymeric nanoparticles for the therapeutic drug monitoring of anticancer drugs." Doctoral thesis, Università degli Studi di Trieste, 2016. http://hdl.handle.net/11368/2907991.
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La chemoterapia consiste nell’impiego di uno o di una combinazione di farmaci antitumorali per il trattamento del cancro. Tuttavia tali farmaci sono caratterizzati da una famacocinetica molto variabile e da una elevata tossicità che porta alla comparsa di molti effetti indesiderati nei pazienti, diminuendo l’efficienza della terapia. In questo contesto l’impiego del “Therapeutic Drug Monitoring” (TDM) risulta particolarmente importante in quanto permette per lo sviluppo di terapie personalizzate per i pazienti aumentando l’efficienza della terapia e la qualità della vita dei pazienti.
Questo progetto è finalizzato alla sintesi e allo sviluppo di sensori, basati su nanoparticelle polimeriche ad impronta molecolare, per i farmaci antitumorali: sunitinib, paclitaxel, SN38 e irinotecano, suo profarmaco.
Tali nanoparticelle solubili sono state ottenute mediante polimerizzazione radicalica ad elevata diluizione utilizzando diversi monomeri funzionali: N-acriloil-tirosina metil estere, N-acriloil triptofano metil estere, 4-vinilpiridina e 7-acrilossicumarina. La reazione è stata effettuata lasciando interagire i monomeri funzionali e il farmaco mediante interazioni deboli (legami idrogeno, π-staking, interazioni di Van der Waals) in DMSO e dopo l’aggiunta dell’acrilamide come co-monomero, dell’N,N’-etilenebisacrilamide come crosslinker e dell’iniziatore radicalico azobisisobitironitrile (AIBN) la polimerizzazione è stata ottenuta scaldando a 70°C per 4 giorni. La molecola templato è stata rimossa mediante dialisi prima in una miscela di metanolo e acido acetico, e poi in acqua. Le particelle ottenute dopo liofilizzazione, sono state caratterizzate mediante 1H-NMR, Nanosigh e Dynamic Laser Ligh Scattering. La capacità di legame e la selettività dei polimeri è stata studiata mediante test di recupero utilizzando un metodo HPLC per la quantificazione del farmaco catturato. Mentre le proprietà fluorescenti di alcuni dei polimeri sintetizzati sono state utilizzate per studiare le affinità di legame dei polimeri a basse concentrazioni di farmaco.
Il polimero contenente cumarina e specifico per il sunitinib è stato utilizzato come sensore fluorescente per lo sviluppo di un test di validazione in DMSO:plasma. Il sensore ha mostrato un’accuratezza del 15%, una precisione del 10% e una buona robustezza. Inoltre due diversi sensori fluorescenti sono stati sviluppati per la quantificazione dell’irinotecano in metanolo:plasma. Il primo sensore si basa sul quenching della fluorescenza intrinseca dell’irinotecano, mentre il secondo è un polimero molto fluorescente contenente un monomero funzionale con un gruppo naftalimidico la cui fluorescenza è spenta in seguito all’interazione con l’irinotecano.
Inoltre un test fluorimetrico e colorimetrico è stato sviluppato per quantificare il paclitaxel mediante la tecnica del “dye displacement”. Il test infatti, si basa sulla competizione tra il farmaco libero ed il farmaco legato covalentemente al DABCYL per il legame ad un polimero ad imprinting molecolare contenente EDANS come monomero funzionale fluorescente. Infatti il DABCYL è sia un colorante rosso, sia un FRET quencher dell’EDANS, perciò il suo legame nel polimero porta ad una variazione del colore e della fluorescenza del polimero.
Infine un test colorimetrico per la quantificazione dell’irinotecano è stato sviluppato utilizzando un polimero ad imprinting molecolare contenente l’acido 2-acrilamido-2-metil propansolfonico come monomero funzionale. Il test si basa sul legame del colorante: anilina gialla nei siti di legame del polimero rimasti liberi dopo interazione con i campioni di farmaco. L’interazione tra il colorante e l’acido solfonico nel polimero genera un cambio di colore da giallo a rosso.<br>Chemotherapy consists in cancer treatment by the administration of a single or a combination of anticancer drugs. However chemotherapy agents are often characterized by an high variability of pharmacokinetic among patients and an high toxicity that leads to the appearance of many side effects decreasing the therapy efficiency. Therefore the therapeutic drug monitoring (TDM) become useful to develop personalized therapies for patients in order to increase the efficiency of the therapy and patient compliance.
This project is aimed on the synthesis and development of specific sensors based on molecularly imprinted polymeric nanoparticles, to be applied in TDM of the anticancer drugs: sunitinib, paclitaxel, SN38 and its prodrug irinotecan.
Soluble nanoparticles were obtained by high dilution radical polymerization with different functional monomers: N-acryloyl-tyrosine methyl ester, N-acryloyl-tryptophan methyl ester, 4-vinyl pyridine or 7-acryloyloxy-coumarin. The reactions were carried out allowing the functional monomer to interact with the drug by weak interactions (H-bonds, -staking and Van der Waals) in DMSO and after the addition of the co-monomer acrylamide, the crosslinker N,N’-ethylene bisacrylamide, and the radical initiator azobisisobutyronitrile (AIBN) the polymerization was achieved heating at 70°C for 4 days. The template was removed by dialysis first in methanol:acetic acid mixture and after in water. After the freeze-drying the polymers were characterized by 1H-NMR, Nanosight, and Dynamic Laser Light Scattering. The polymers binding capabilities and selectivity were investigated by rebinding tests using an HPLC method for the quantification of drug captured. while the fluorescence properties of some of these polymers were exploited to study the polymers binding affinities at low drug concentrations.
The polymer containing coumarin and imprinted with sunitinib was used as fluorescence sensor to set up a validation test in DMSO:plasma mixture. The system showed an accuracy of 15%, a precision of 10% and a good robustness. Two different fluorescence sensors were also developed for irinotecan able to quantify the drug in methanol:plasma mixtures. The first sensor is based on the quenching of the intrinsic fluorescence of irinotecan, while the second is an highly fluorescence polymer containing a functional monomer with a naphthalimide mojety whose fluorescence is quenched upon interaction with the drug.
Moreover the dye displacement technique was used to set up a fluorescent and colorimetric test for paclitaxel quantification. The test is based on the competition between the free paclitaxel and the drug covalently linked to DABCYL dye, for the binding in to an imprinted polymer containing EDANS fluorescent functional monomer. Since DABCYL is both a red dye and a FRET quencher of EDANS, its binding into the polymer gives a change in the polymer fluorescence and colour.
Finally a colorimetric test for irinotecan quantification was developed using an imprinted polymer containing 2-acrylamido-2-methylpropane sulfonic acid as functional monomer. The test is based on the binding of aniline yellow dye in to the remaining free binding sites of the polymer after treatment with drug samples. The interaction between the dye and the sulfonic acid in to the polymer gives a change of colour from yellow to red.
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IACUZZI, VALENTINA. "Design of detection systems for the therapeutic drug monitoring of anticancer drugs." Doctoral thesis, Università degli Studi di Trieste, 2020. http://hdl.handle.net/11368/2967986.
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Considerato che la maggior parte dei farmaci antitumorali risulta caratterizzata da un'alta variabilità interindividuale nelle concentrazioni plasmatiche, che si riflette sull'efficacia del trattamento, durante il progetto di dottorato qui descritto sono state sviluppate tecniche per il loro monitoraggio terapeutico (TDM).
In primo luogo, è stato sviluppato, validato e cross-validato un metodo LC-MS/MS per la quantificazione di imatinib (IMA) e del suo metabolita attivo, norimatinib (norIMA), in pazienti affetti da tumore stromale gastrointestinale utilizzando la tecnica del dried blood spot (DBS). Il DBS consente di ridurre costi e tempi di campionamento e migliorare la compliance dei pazienti, poiché l’analisi viene effettuata tramite una goccia di sangue capillare depositata su carta. Da questa gli analiti vengono estratti con MeOH acidificato e l'estratto viene iniettato in un sistema LC (configurato con una cromatografia 2D per la pulizia on-line del campione), accoppiato ad un API-4000QT. Il metodo ha mostrato una buona linearità (R2> 0,996) nei range di 50-7500 ng/mL e 10-1500 ng/mL per IMA e norIMA. La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.1% e tra 88.9-112.8%, mentre quelle inter-day erano ≤6,6% e tra 95.7-104.3%, per entrambi gli analiti. Sono stati valutati inoltre: l'influenza dell'ematocrito (Hct), del volume depositato e dell'omogeneità del campione sull’analisi; la correlazione tra la concentrazione in DBS da prelievo venoso e da finger-prick (differenza tra -12 e 3.8%) e la stabilità dei DBSs (fino a 16 mesi). Il metodo è stato applicato per la quantificazione di 67 campioni DBSs di pazienti. Le concentrazioni in DBS, normalizzate per Hct e per un fattore di correzione che prescinde dall’Hct, correlano con quelle plasmatiche.
Parte del lavoro di questo progetto è stato anche dedicato allo sviluppo di strategie alternative a LC-MS/MS per favorire ulteriormente l’applicazione del TDM. In particolare, è stata eseguita la sintesi di polimeri (molecularly imprinted polymers - MIPs), con l'obiettivo futuro di applicarli come recettori in un sistema di rilevamento fluorimetrico per IMA. I MIPs sono stati sintetizzati sfruttando l'approccio non covalente e la polimerizzazione radicale ad alta diluizione. Tramite questa tecnica, i MIPs ottenuti, sintetizzati in DMSO e con acido metacrilico come monomero funzionale, presentano dimensioni nanometriche (dati acquisiti tramite dynamic light scattering). I tests di rebinding hanno dimostrato che solo 2 MIPs sono stati in grado di legare IMA con una buona specificità (rispetto ai corrispondenti polimeri non-imprinted) e selettività.
È stato infine sviluppato e validato un metodo LC-MS/MS per la quantificazione di ribociclib (RIBO), palbociclib (PALBO) e letrozolo (LETRO) in plasma. RIBO e PALBO sono farmaci appartenenti alla famiglia dei CDKIs recentemente approvati per il trattamento del carcinoma mammario in combinazione con LETRO. Il metodo messo a punto risulta adatto per l’applicazione nella pratica clinica, grazie ad una semplice preparazione del campione e ad una rapida analisi (6.5 min). Il metodo risulta lineare (R2 tra 0.992-0.983) nei range di concentrazione di 0.3-250 ng/mL per PALBO, 10-10000 ng/mL per RIBO e 0.5-500 ng/mL per LETRO (che coprono le concentrazioni plasmatiche terapeutiche). La precisione e l’accuratezza intra-day sono state, rispettivamente, ≤3.6% e tra 94.5-112.3% per tutti e gli analiti, mentre quelle inter-day erano rispettivamente ≤7.3% e tra 94.5-112.9%. Il metodo è stato applicato con successo alla quantificazione di campioni plasmatici di pazienti.
In conclusione, con lo sviluppo di queste strategie si spera di implementare l’utilizzo del TDM per i farmaci oncologici nella pratica clinica.<br>Despite the continuous progress in drug therapy, most anticancer drugs appear to be characterized by a high interindividual variability in plasma concentrations that is reflected in the efficacy of the treatment. From this arises the need of a personalized approach, so that the drug concentrations in plasma are adequate in each patient. On this basis, during the PhD project reported hereby, different techniques for therapeutic monitoring (TDM) of anticancer drugs were developed.
First, a LC-MS/MS method for the quantification of imatinib (IMA) and its active metabolite, norimatinib (norIMA), was developed, validated and cross-validated in patients affected by gastrointestinal stromal tumour. This method allows to perform the quantification directly on a drop of capillary blood, exploiting the dried blood spot (DBS) technique, reducing sampling time, costs and improving patients’ compliance. Analytes were extracted from DBS samples by adding acidified methanol and the extract is injected into a LC system (configured with a 2D chromatography for online cleaning of the sample), coupled with an API-4000QT. The method showed good linearity (R2> 0.996) in the ranges of 50-7500 ng/mL and 10-1500 ng/mL for IMA and norIMA. Intra-day precision and accuracy were ≤3.1% and between 88.9-112.8%, respectively, while inter-day ones were ≤6.6% and between 95.7-104.3 %, for both analytes.
Moreover, were also evaluated: the influence of the haematocrit (Hct), of the spot size and of the sample homogeneity on the analysis; the correlation between the concentration in DBS from venous sampling and from finger-prick (% difference between -12 and 3.8%) and the stability of DBSs (up to 16 months). Then, the method was applied for the quantification of 67 DBSs patients’ samples. Good agreement was obtained between IMA and norIMA concentrations found in DBS and plasma samples applying either the Hct normalization or avoiding it, simply multiplying the DBS concentration with a correction factor.
Part of the work of this project was also dedicated for the development of alternative strategies for the quantification of anticancer drugs, to promote the application of TDM. In particular, the synthesis of molecularly imprinted polymers (MIPs) was performed, with the future goal of applying them as receptors in a fluorimetric detection system for IMA. MIPs were synthesized using the non-covalent approach and high dilution radical polymerization. Through this synthesis, the MIPs obtained, synthesized in DMSO with methacrylic acid as functional monomer, shown nanometric size (data acquired by dynamic light scattering). The rebinding tests then showed that 2 MIPs in particular were able to bind IMA with a good specificity (compared to the corresponding non-imprinted polymers) and selectivity.
Finally, a LC-MS/MS method was developed and validated for the quantification of ribociclib (RIBO), palbociclib (PALBO) and letrozole (LETRO) in human plasma. RIBO and PALBO are drugs belonging to the CDKIs family, recently approved for breast cancer treatment in combination with LETRO. The method developed is suitable for its application in clinical practice, thanks to simple sample preparation and rapid analysis (6.5 min). The method showed a good linearity (R2 between 0.992-0.983) in the concentration ranges of 0.3-250 ng/mL for PALBO, 10-10000 ng mL for RIBO and 0.5-500 ng/mL for LETRO (covering the therapeutic plasma concentrations). Intra-day precision and accuracy were ≤3.6% and between 94.5-112.3% for all and analytes, respectively, while inter-day ones were ≤ 7.3% and 94.5-112.9%. The method has been successfully applied for patients’ plasma samples quantification.
In conclusion, with the development of these strategies there is the hope to implement the application of TDM for anticancer drugs in the clinical practice.
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Gilissen, Leonardus (Lennard) Petrus Lucia. "Therapeutic drug monitoring of thiopurine therapy in IBD patients." [Maastricht : Maastricht : Maastricht University] ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=11069.
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Eichner, Kajal Kiran [Verfasser]. "Therapeutic drug monitoring of mycophenolic acid / Kajal Kiran Eichner." Ulm : Universität Ulm, 2019. http://d-nb.info/1175526754/34.
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Archibald, Timothy L., Derek Edward Murrell, and Stacy D. Brown. "Chromatographic Methods in Hiv Medicine: Application to Therapeutic Drug Monitoring." Digital Commons @ East Tennessee State University, 2018. https://doi.org/10.1002/bmc.4170.
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HIV antiretroviral therapy spans several different drug classes, meant to combat various aspects of viral infection and replication. Many authors have argued the benefits of therapeutic drug monitoring (TDM) for the HIV patient including compliance assurance and assessment of appropriate drug concentrations; however, the array of drug chemistries and combinations makes TDM an arduous task. HPLC-UV and LC-MS/MS are both frequent instruments for the quantification of HIV drugs in biological matrices with investigators striving to balance sensitivity and affordability. Plasma, the dominant matrix for these analyses, is prepared using protein precipitation, liquid-liquid extraction or solid-phase extraction depending on the specific complement of analytes. Despite the range of polarities found in drug classes relevant to HIV therapeutics, most chromatographic separations utilize a hydrophobic column (C18 ). Additionally, as the clinically relevant samples for these assays are infected with HIV, along with possible co-infections, another important aspect of sample preparation concerns viral inactivation. Although not routine in clinical practice, many published analytical methods from the previous two decades have demonstrated the ability to conduct TDM in HIV patients receiving various medicinal combinations. This review summarizes the analytical methods relevant to TDM of HIV drugs, while highlighting respective challenges.
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Pingeon, Marine. "Development and validation of analytical methods for therapeutic drug monitoring." Doctoral thesis, Universita degli studi di Salerno, 2019. http://elea.unisa.it:8080/xmlui/handle/10556/4509.
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2017 - 2018<br>The U.S. Food and Drug Administration defines as Precision or Personalized Medicine (PM) an
innovative therapeutic approach that tailors therapy and prevention on patients based on inter-individual
variabilities in molecular or environmental features and in lifestyles. The major goals of PM are to maximize
treatment efficacy and to reduce cost, toxicities and therapy failure rates by early identification of patients who
might benefit or not of a specific treatment. In this scenario, therapeutic drug monitoring (TDM) is an important
laboratory tool for PM because of the possibility to measure several drugs and bioactive molecules in human
biological matrices. TDM is based on the hypothesis that in the majority of drugs, there is a relationship
between administered dose and circulating concentration of unbound fraction - and between this concentration
and observed pharmacological effects. TDM is recommended for drugs with significant inter-individual
pharmacokinetic variability and an established relationship between blood concentrations and clinical efficacy
and/or toxicity. Moreover, TDM is also advisable in special populations such as pregnant women and children.
To date, liquid chromatography and immunometric assay are still considered the standard for molecule
measurement in biological fluids; however, in recent years, LC tandem mass spectrometry (LC-MS) is gaining
popularity because of the possibility of in-depth and multiplexed analysis with high selectivity and specificity.
During this Ph.D. program, we developed several high performance LC (HPLC)- and LC-MS/MS-based
approaches for TDM of different drugs measured in various types of body fluids and validated according to
EMA and FDA guidelines. In particular, we focused on:
1) TDM of hydroxychloroquine (HCQ) blood concentration, a drug with a wide therapeutic window.
Our method was validated on a cohort of patients with Systemic Lupus Erythematosus treated with
HCQ and blood concentrations were correlated to several clinical parameters, such quality of life.
Moreover, TDM of HCQ was also used to monitor treatment adherence in those subjects.
2) TDM of a commonly used chemotherapeutic agent, the 5-fluorouracil (5-FU), which is known to
have a narrow therapeutic window and a high toxicity
3) TDM of a new kinase inhibitor, Ruxolitinib, approved for the treatment of myeloproliferative
hematologic disorders.
4) TDM of several drugs, such as caffeine and phenobarbital, in newborns who are at particular risk of
uncorrected drug dosage. Due to the need to carry out analyses on very-small volume samples, we
validated an analytical method using micro-sampling techniques such as the dried blood spot (DBS)
sampling combined with LC-MS/MS analysis. [edited by author]<br>XVII n.s. (XXXI ciclo)
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Charbe, N. B. "THERAPEUTIC DRUG MANAGEMENT OF HIV-INFECTED PATIENTS WITH COMORBIDITIES." Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/354114.
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Today, antiretroviral therapy is potent, convenient and usually well tolerated, capable of reducing human immunodeficiency virus (HIV) blood concentration to undetectable values within a few weeks from treatment initiation and of inducing a robust and sustained CD4 T-cell gain. Despite these unquestioned successes, the problem is far from being solved: even in countries with full access to ntiretroviral treatment, life expectancy of people under ARV therapy remains lower with respect to that of uninfected people. Furthermore, large populations of HIV infected individuals who are not diagnosed remain untreated or enter treatment at a very late stage of diseases. Undiagnosed and untreated population represents an infected reservoir that increases HIV transmission.
Patient with HIV/Acquired Immunodeficiency Syndrome (AIDS) disease face many problems when commencing antiretroviral therapy also called as highly active ntiretroviral therapy (HAART). In addition to understanding their HIV disease, they are prescribed with combination antiretroviral therapy and have a higher risk of developing adverse drug reactions. Consequently, patients feel that HIV treatment is a burden and turn non-adherent to HAART. One important tool for better patient compliance towards HAART is optimizing therapy for minimal side effects by therapeutic drug monitoring.
In the present PhD research work entitled “Traditional and novel therapeutic approaches for the personalized therapy in HIV patients co-infected with opportunistic infections and other co-morbidities” we studied the role of therapeutic drug monitoring in HAART therapy for personalized patient care. The experimental section of the thesis is broadly categories as follows
• HPLC UV assay method development for ARV drugs quantification
• LC-MS/MS assay method development for ARV drugs quantification
• Pharmacokinetics of ARV drugs dosing at conventional doses
• Association between antiretroviral pharmacokinetics and drug-related metabolic disorders
• Pharmacokinetic interaction between raltegravir and anti HCV drugs in an HIV-HCV liver transplant recipientIn conclusion we developed and validated HPLC-UV and LC-MS/MS methods which are accurate, reproducible and able to simultaneously quantify nineteen antiretroviral agents in plasma by a single assay. Good extraction efficiency and low limit of quantification make these methods suitable for use in clinical trials and for TDM. This method has been successfully applied for our routine TDM and PK studies in HIV-infected patients.
When applied these methods for routine therapeutic drug monitoring of antiretroviral drugs we were able to document that a significant proportion of patients treated with some of the antiretrovirals at marketed doses had plasma concentrations exceeding the upper therapeutic threshold. Such selected patients, who might have the highest risk of experiencing drug-related complications, may benefit from therapeutic drug monitoring -driven adjustments in antiretroviral doses with potential advantages in terms of costs and toxicity.
In case of atazanavir, a protease inhibitor, we documented that significant proportion of patients treated with conventional atazanavir dosages had plasma concentrations exceeding the upper therapeutic threshold. A likely possibility is an inherited deficit in atazanavir clearance and/or atazanavir metabolism; in particular, atazanavir is a dedicated CYP3A substrate, which includes 3A4 and 3A5, two polymorphic genes. The administration of unboosted atazanavir to healthy subjects carrying the defective CYP3A5*3 resulted in significantly higher ATV concentrations compared with values measured in patients expressing CYP3A5 . Assuming that over 90% of patients in our study were Caucasians with a high prevalence of carriers of CYP3A5*3, it is likely that the observed overexposure to atazanavir concentrations is the result of excessively high dose of ritonavir- boosted atazanavir or of needless boosting with ritonavir. This is a first important conclusion of our study that raises concerns on the need of full dose of ritonavir-boosted atazanavir in caucasian patients and opens new questions about the atazanavir dosages that should considered correct (or in label and off label in Europe). We found the positive correlation of atazanavir concentration with hyperbilirubinemia and lipid dystrophy. We confirmed that the overexposure to ATV is associated with increased risk of nephrolitiasis. We also found that such patients have the highest risk of experiencing atazanavir -related complications and may benefit from therapeutic drug monitoring -driven adjustments in atazanavir dosage with potential advantages in terms of costs and toxicity.
At the end when we monitored raltegravir concentration in HIV infected patient co-infected with hepatitis C virus we observed a threefold increase in exposure of raltegravir concentration. HIV-HCV co-infected liver transplant recipients was simultaneously taking ombitasvir, dasabuvir and paritaprevir/ritonavir (3D regimen) for recurrent Hepatitis C virus infection. Such suspected interaction, which might be clinically relevant in selected patients, is easily manageable through therapeutic drug monitoring of raltegravir concentrations, eventually improving the safety of this drug.
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Öhman, Daniel. "Bioanalytical development for application in therapeutic drug monitoring : focus on drugs used in psychiatry /." Linköping : Univ, 2003. http://www.bibl.liu.se/liupubl/disp/disp2003/med775s.pdf.
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Peláez, Gutiérrez Enelia Cristina. "Nanoplasmonic biosensors for clinical diagnosis, drug monitoring and therapeutic follow-up." Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/672028.
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Aquesta tesi doctoral té com a objectiu el desenvolupament de diversos biosensors que operen sense necessitat de marcatge addicional basats en dispositius plasmònics òptics per a la detecció directa de medicaments o biomarcadors relacionats amb diferents malalties i que són analitzats directament en mostres humanes com plasma, sèrum, orina o esput. Aquests dispositius biosensors ofereixen un sens fi de beneficis com és la seva alta sensibilitat, facilitat d’operació, l’obtenció de dades quantitatives, detecció sense marcatge en temps real, i comunament només necessiten d’un petit volum de mostra. Tot això converteix els biosensors plasmònics en eines analítiques molt adequades per al diagnòstic de malalties, el control de la medicació o el seguiment de teràpies personalitzades. El nostre grup d’investigació ha demostrat amb èxit la implementació de biosensors òptics basats en plasmònica i en fotònica de silici, inclòs el desenvolupament complet de bioaplicaciones, el que ha aplanat el camí de la seva futura transferència tecnològica per a la seva implementació com a dispositius Point-of-Care ( POC). Els biosensors desenvolupats en aquesta Tesi inclouen la seva optimització i validació completa amb mostres reals, exemplificant alguns desafiaments clínics en els quals aquests biosensors plasmònics poden superar importants limitacions de les tècniques d’anàlisi convencionals actuals, mostrant el seu potencial i versatilitat com a futurs dispositius POC per ser usats en les unitats d’atenció primària en salut o fins i tot en l’entorn domèstic per al propi autocontrol per part dels pacients.
La tesi està organitzada en sis capítols. El capítol 1 conté la introducció dels conceptes bàsics i l’estat de l’art sobre els avenços actuals en les tècniques de diagnòstic i control de malalties i / o teràpies i el paper que exerceixen els biosensors per millorar-los. El capítol 2 inclou una descripció detallada de les plataformes biosensoras emprades i una descripció general dels processos metodològics. El Capítol 3 descriu el desenvolupament d’un dispositiu nanoplasmónico per al control terapèutic de l’medicament acenocumarol, un anticoagulant comunament administrat directament en plasma humà. El Capítol 4 es centra en el desenvolupament d’un biosensor plasmónico que serveixi com a control de la dieta lliure de gluten que han de portar els pacients celíacs. El Capítol 5 descriu les estratègies desenvolupades per a la detecció de dos biomarcadors per al diagnòstic primerenc de tuberculosi en mostres d’esput. Finalment, el Capítol 6 explora la detecció de quatre autoanticossos específics associats amb l’aparició de l’tumor directament en el sèrum humà com biomarcadors potencials per al diagnòstic primerenc de el càncer colorectal.<br>Esta Tesis Doctoral tiene como objetivo el desarrollo de diversos biosensores que operan sin necesidad de marcaje adicional basados en dispositivos plasmónicos ópticos para la detección directa de medicamentos o biomarcadores relacionados con diferentes enfermedades y que son analizados directamente en muestras humanas como plasma, suero, orina o esputo. Estos dispositivos biosensores ofrecen un sinnúmero de beneficios como es su alta sensibilidad, facilidad de operación, la obtención de datos cuantitativos, detección sin marcaje en tiempo real, y comúnmente sólo necesitan de un pequeño volumen de muestra. Todo esto convierte a los biosensores plasmónicos en herramientas analíticas muy adecuadas para el diagnóstico de enfermedades, el control de la medicación o el seguimiento de terapias personalizadas. Nuestro grupo de investigación ha demostrado exitosamente la implementación de biosensores ópticos basados en plasmónica y en fotónica de silicio, incluido el desarrollo completo de bioaplicaciones, lo que ha allanado el camino de su futura transferencia tecnológica para su implementación como dispositivos Point-of-Care (POC). Los biosensores desarrollados en esta Tesis incluyen su optimización y validación completa con muestras reales, ejemplificando algunos desafíos clínicos en los que dichos biosensores plasmónicos pueden superar importantes limitaciones de las técnicas de análisis convencionales actuales, mostrando su potencial y versatilidad como futuros dispositivos POC para ser usados en las unidades de atención primaria en salud o incluso en el entorno doméstico para el propio autocontrol por parte de los pacientes.
La tesis está organizada en seis capítulos. El Capítulo 1 contiene la introducción de los conceptos básicos y el estado del arte sobre los avances actuales en las técnicas de diagnóstico y control de enfermedades y/o terapias y el papel que desempeñan los biosensores para mejorarlos. El Capítulo 2 incluye una descripción detallada de las plataformas biosensoras empleadas y una descripción general de los procesos metodológicos. El Capítulo 3 describe el desarrollo de un dispositivo nanoplasmónico para el control terapéutico del medicamento acenocumarol, un anticoagulante comúnmente administrado directamente en plasma humano. El Capítulo 4 se centra en el desarrollo de un biosensor plasmónico que sirva como control de la dieta libre de gluten que deben llevar los pacientes celíacos. El Capítulo 5 describe las estrategias desarrolladas para la detección de dos biomarcadores para el diagnóstico temprano de tuberculosis en muestras de esputo. Finalmente, el Capítulo 6 explora la detección de cuatro autoanticuerpos específicos asociados con la aparición del tumor directamente en el suero humano como biomarcadores potenciales para el diagnóstico temprano del cáncer colorrectal.<br>This Doctoral Thesis aims to the development of several label-free biosensing analytical strategies integrated within optical plasmonic devices for the direct detection of drugs or biomarkers related to different diseases in biological samples such as plasma, serum, urine, and sputum. These biosensor devices offer several benefits like their high sensitivity, ease of operation, quantitative data, label-free operation, and real-time detection, and commonly require a small sample volume. All this turn plasmonic biosensors into well-suited analytical tools for diagnosing diseases, monitoring medication, or for personalized therapies follow-up. Our research group has extensively demonstrated the successful conjunction of novel in-house optical biosensor configurations (like plasmonic and photonic-based designs) with the full demonstrations of bioapplications, which has paved the way for their potential technological transfer as Point-of-Care devices (POC) for clinical diagnostics. The biosensor assays here implemented, which include their full optimization and validation with real samples, exemplify clinical challenges where such biosensors can overcome limitations of current conventional analytical techniques. The results show the potential and versatility that plasmonic biosensors can offer as future POC devices placed in primary healthcare units or even in the household environment for patients’ self-monitoring.
This thesis is organized into six chapters. Chapter 1 is the introductory one, which explains the basic concepts and the state of the art of the current advances in diagnosis and monitoring techniques of diseases and/or therapies and the role of biosensors to improve them. Chapter 2 includes a detailed description of the biosensor platforms employed and a general description of the methodological processes. Chapter 3 is related to the development of a nanoplasmonic device for the therapeutic monitoring of the drug acenocoumarol, a commonly administered anticoagulant, directly in human plasma. Chapter 4 focuses on the implementation of a plasmonic biosensor that monitors the gluten-free diet in urine in celiac patients. Chapter 5 describes the biosensing strategies developed for the detection of two biomarkers for the early diagnosis of tuberculosis in sputum samples. Finally, Chapter 6 explores the detection of four specific autoantibodies associated with the tumor onset directly in human serum as potential biomarkers for the early detection of colorectal cancer.<br>Universitat Autònoma de Barcelona. Programa de Doctorat en Química
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Pacoste, Laura Gabriella Calmanovici. "Development of Copper Selenide Quantum Dots-Based Therapeutic Drug Monitoring Biosensors for Toremifene - A Breast Cancer Drug." University of the Western Cape, 2017. http://hdl.handle.net/11394/6172.
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Magister Scientiae - MSc (Chemistry)<br>With rising knowledge of the effects on plasma concentration caused by allelic variations in the
cytochrome P450 genes and other metabolic factors such as drug-drug or drug-food
interactions, more attention is paid to the possibility of therapeutic drug monitoring (TDM).
Thus, there is a rising demand for quick, low-cost and efficient equipment for drug targeting.
For such devices, electrochemical biosensing techniques serve as a promising alternative.
Toremifene is the chlorinated analogue of tamoxifen and is used for adjuvant antiestrogenic
treatment for breast cancer and could serve as a candidate for TDM treatments. In this work, a
proof of concept enzymatic electrochemical biosensor is developed for the detection of
toremifene in aqueous solution. The biosensor uses water-soluble 6-mercaptopropinoic acid
capped copper selenide quantum dots (6MHACuSe QDs) conjugated to a cysteamine selfassembled
monolayer on a gold electrode. The 6MHACuSe QDs where further conjugated with
CYP2C9 enzyme, which has shown to have a major part in the hydroxylation of toremifene
(TOR) to form 4-hydroxytoremifene (4OH-TOR). The 6MHACuSe QDs where synthesized
using a facile and rapid aqueous route. Results from synthesis of 3-mercaptiorproionic acid
(3MPA) and mercaptosuccinic acid (MSA) capped copper selenide QDs, are also presented in
the study and compared to the results of the 6MHA capped copper selenide QDs. X-ray
diffraction analysis (XRD) confirmed formation of copper selenide species of nonstoichiometric
form Cu2-xSe (for the 6MHA and 3MPA capped CuSe QDs) and ?-CuSe
stoichiometric form (for the MSA capped CuSe QDs).
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Kredo, Tamara. "The clinical role of therapeutic drug monitoring of antiretrovirals : a Cochrane systematic review." Master's thesis, University of Cape Town, 2008. http://hdl.handle.net/11427/3285.
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Pickering, M., and Stacy D. Brown. "Validated HPLC-UV and LC-MS Assays for Therapeutic Drug Monitoring of Ertapenem in Human Plasma." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etsu-works/5287.
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Chermá, Yeste Maria Dolores. "Therapeutic Drug Monitoring in Psychiatry : Some aspects of utility in clinical practice and research." Doctoral thesis, Linköpings universitet, Klinisk farmakologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-52107.
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Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described. Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study. The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype. The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug. Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.
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Lee, W. W. Y. "Polymer films containing SERS active metal nanoparticles for therapeutic drug monitoring and forensic analysis." Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678709.
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The work in this thesis was centred on developing an alternative method for therapeutic drug monitoring based on using microneedle arrays to sample interstitial fluid combined with a SERS active layer for analysis of the sampled fluid. Simple aqueous colloids are too unstable to use in this application so here the colloid was aggregated and then preserved within hydroxyethylcellulose (HEC) films. The films were then tested alongside microneedle arrays, which were prepared and developed by Salvador and Donnelly in the School of Pharmacy, Queen's University Belfast. The principle was that the microneedle arrays would puncture the skin to take up the interstitial fluid containing therapeutic drugs and deliver it to the base plate where the SERS sensing HEC film would be located. The SERS films themselves were found to be effective for the analysis of the target thetapeutic drugs, theophylline and phenytoin. However, when the drugs were taken up by microneedle arrays they were largely trapped within them. The SERS films were found to have a much broader range of potential applications than therapeutic drug monitoring. They were shown not simply to be able to detect conventional aqueous solutions of drugs but they were used as the basis for a novel trace drug detection method. In this method the area to be tested was wiped with a moistened swab which was then contacted with the SERS active film. With mephedrone as a test analyte, drug deposits on surfaces in the Ilg range could be collected and detected. Alternatively, for seized bulk methiopropamine drug samples which had high fluorescence, the films provided a convenient method of quenching the fluorescence and enhancing spectra simultaneously. Finally, the films were also tested for use in analysis of ink samples and proved to be highly effective, providing spectra that allowed various inks to be discriminated.
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Handley, Danielle Suzannah. "Antipsychotic therapeutic drug monitoring : evaluation of the role of oral fluid, and plasma quetiapine metabolite assays." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/antipsychotic-therapeutic-drug-monitoring(776c673a-f81a-4eea-8994-2d60528c2178).html.
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Therapeutic drug monitoring (TDM) is the measurement of drugs and/or metabolites in biological samples to guide therapy. TDM for antipsychotic drug therapy in schizophrenia treatment is well-established if adherence is in doubt and in dose optimisation. The antipsychotic quetiapine has a short plasma half-life and no clear reference range for clinical response. Three quetiapine metabolites, N-desalkylquetiapine, O-desalkylquetiapine and 7-hydroxyquetiapine, were investigated in routine plasma TDM samples to determine whether they provide useful information to assess quetiapine exposure. Compared to median plasma quetiapine concentrations, N-desalkylquetiapine, O-desalkylquetiapine and 7-hydroxyquetiapine plasma concentrations were equivalent, 1/10th and 1/20th, respectively. All metabolites showed greater correlation to dose than quetiapine itself; dose-related plasma concentrations have been presented to aid future results interpretation. Blood sampling is invasive; hence, oral fluid was investigated as an alternative matrix. A clinical study was undertaken to investigate the relationship between analyte concentrations in oral fluid samples collected using different oral fluid collection devices [Greiner Bio-One (GBO; in-mouth buffered collected system), and Thermo Oral-Eze] and in plasma. Existing plasma LC-M/MS methods were combined, and sample preparation modified to be suitable for acidified (buffered) oral fluid samples. The methods were assessed to ensure they were fit-for-purpose. Relationships between plasma and oral fluid concentrations of clozapine and norclozapine were poor, and no better than results obtained using unstimulated oral fluid collected via the drool method. Median concentrations of all analytes were lower in the GBO samples than Oral-Eze samples; however, clozapine and norclozapine concentrations in samples collected using the proprietary devices were approximately twice the concentration measured in samples collected by the drool method, as a ratio to plasma concentrations. Concentration differences are possibly related to differing salivary stimulation during sample collection. A positive finding was a patient who had become non-adherent to clozapine was identified from oral fluid as well as plasma analysis.
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Pickering, Matthew K., and Stacy D. Brown. "Assays for Determination of Ertapenem for Applications in Therapeutic Drug Monitoring, Pharmacokinetics, and Sample Stability." Digital Commons @ East Tennessee State University, 2014. https://doi.org/10.1002/bmc.3301.
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Carbapanems are a class of β-lactam antibiotics with broad-spectrum potency and high β-lactamase resistance. Ertapenem, a member of this class, sold under the trade name Invanz™, has been of interest in the world of antibiotic therapeutic drug monitoring owing to its highly standardized 1 g dose and its high degree of plasma protein binding. Owing to the relative newness of this drug, fewer than 30 methods for ertapenem quantification have been published. Among these about half utilize biological matrices at the sample type. Liquid-liquid extraction and protein precipitation prevail as the most frequently used sample preparation techniques, despite their low recoveries compared with solid-phase extraction. Additionally, high-performance liquid chromatography with ultraviolet detection (HPLC-UV) is the instrumentation choice for most ertapenem assays. While these approaches may not achieve the highest possible sensitivity for ertapenem quantification, they provide clinically relevant tools for monitoring ertapenem in real patients. Sample stability is an ongoing concern for laboratories that handle ertapenem analysis, with buffering being of paramount importance, as well as low temperature (
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Orrell, Catherine. "Using electronic methods of adherence monitoring and therapeutic drug monitoring (TDM) to eliminate discordance between antiretroviral adherence and virological failure." Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/20349.
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Background: Adherence to antiretroviral therapy (ART) is critical: only 70% achieve viral suppression at a year. Current adherence methodologies, with slow reaction to missed dosing, inadequately predict virological outcomes. Ideal adherence methods would be cheap, easy to use, and allow rapid response to missed doses to improve outcomes. We explored ideal adherence monitoring methodology for a large public sector ART clinic in Cape Town. Methods: We designed a randomised controlled study for ART-naïve individuals to determine whether text messaging after a missed dose would improve adherence recorded by an electronic adherence monitoring device (EAMD), reduce treatment interruptions or impact on virological outcome (using regression modelling). Five other measures of adherence were captured prospectively during the study: selfrecall (SR), clinic-based pill count (CPC), pharmacy refill data (PR-average or PR-gaps) and efavirenz concentration. The predictive value of each adherence methodology on virological and HIV-1 resistance outcomes was compared by calculating the area under the receiver operating characteristic curve, from logistic regression models. The impact of efavirenz concentration and CYP2B6 metaboliser genotype data on failure was examined using Cox proportion hazard modelling; and the most predictive lower limit for EFV concentration was determined. Antiretroviral cohort and pharmacy refill data were compared, using simple statistics, to determine which provided the best method of determining those retained in care.
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Hummert, Shelly, and Myke R. Green. "Therapeutic Drug Monitoring and Dose Adjustment of Posaconazole in Adult Patients with Acute Myeloid Leukemia: A Single-Center Experience." The University of Arizona, 2014. http://hdl.handle.net/10150/614191.
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Class of 2014 Abstract<br>Specific Aims: Evaluate serum posaconazole concentrations following dose adjustment in response to subtherapeutic serum concentrations. Determine optimal dose adjustment schema and identify toxicity with doses above 600 mg daily (e.g.: 200 mg per os three times daily). Methods: The health records were reviewed for 29 patients ≥ 18 years with acute myeloid leukemia over a four-year period. Participants initially received posaconazole 200 mg per os three times daily as prophylaxis and required at least one dose adjustment secondary to a subtherapeutic posaconazole serum concentration. Patients were stratified by posaconazole dosing following dose adjustment (A=200mg QID, B=300mg TID, C=400 mg TID, D=400 QID). Main Results: There was a statistically significant increase in posaconazole serum concentration in each group compared to baseline serum concentration, aside from group C (group A and B P<0.001, group C P=0.236, and group D P=0.0076). The majority of participants in 3 of the 4 groups reached therapeutic serum concentration (A=0.87, B=0.76, D=0.80) whereas group C had a serum posaconazole concentration on average below therapeutic range (0.51). There was no significant difference between the four groups in regards to renal function (p=0.35) or hepatic function (AST p=0.676, ALT p=0.877, total bilirubin p=0.097). Conclusion: A dose increase led to an increase in posaconazole serum concentration except for the dosing regimen of 400 mg three times daily. However, the study is limited by a small patient population, an unequal number of patients in each group, and potentially by poor absorption of posaconazole suspension. Further research is required to expand on these findings.
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ZANCHETTA, MARTINA. "Development of analytical methods for therapeutic drug monitoring of first- and second-line therapies for hepatocellular carcinoma." Doctoral thesis, Università degli Studi di Trieste, 2022. http://hdl.handle.net/11368/3015402.
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Il monitoraggio terapeutico dei farmaci (TDM) è la pratica clinica di misurazione di un farmaco specifico a intervalli di tempo definiti per mantenere le concentrazioni plasmatiche all'interno di una finestra terapeutica mirata, per massimizzare l'efficacia e ridurre al minimo la tossicità. Per rendere fattibile questo approccio sono necessari metodi analitici robusti, sensibili e riproducibili per quantificare i farmaci antitumorali nei fluidi biologici. Questo progetto di dottorato si è concentrato su quattro farmaci antitumorali orali utilizzati per il trattamento di pazienti con HCC avanzato: sorafenib (SORA), regorafenib (REGO), lenvatinib (LENVA) e idarubicina (IDA), la cui sicurezza ed efficacia è oggetto di indagine come opzione terapeutica di terza linea.
SORA, REGO e LENVA sono stati inoltre coinvolti in uno studio di cross-validazione (CRO-2018-83) in corso presso il Centro di Riferimento Oncologico di Aviano, il cui obiettivo primario era la cross-validazione tra il metodo LC-MS/MS di quantificazione basato sul plasma e quello basato sul Dried Blood Spot (DBS) per dimostrare che il DBS può essere utilizzato come metodo di campionamento alternativo rispetto al campione plasmatico per la quantificazione di questi farmaci. Il DBS può migliorare l'applicabilità del TDM grazie alle sue procedure di raccolta del campione meno invasiva per il paziente. Invece, la quantificazione di IDA e del suo metabolita attivo nel plasma umano era richiesta come obiettivo secondario di uno studio clinico di fase II (CRO-2017-42) in corso presso il CRO.
Per tutti questi farmaci, i dati di esposizione-risposta e -tossicità sono ancora limitati o mancanti, evidenziando così la necessità di approfondire questo tipo di indagine.
Per valutare la concentrazione plasmatica del farmaco nelle matrici biologiche sono necessari metodi analitici affidabili.
In questo contesto, sono stati sviluppati e validati due metodi LC-MS/MS secondo linee guida EMA ed FDA per la quantificazione contemporanea di SORA, REGO e 3 metaboliti attivi (SORA-N-ossido, REGO-N-ossido e N-desmetil-REGO-N-ossido), sia in plasma umano sia in DBS. Questi metodi hanno lo stesso range analitico (50-8000 ng/mL) per SORA e REGO e (30-4000 ng/mL) per i metaboliti. Dopo le validazioni, questi metodi sono stati applicati per quantificare 66 campioni di plasma e 63 DBS ottenuti da 16 pazienti, trattati con SORA o REGO e arruolati nello studio CRO 2018 83. Tale analisi ha permesso di ottenere dati preliminari riguardanti le concentrazioni dei farmaci nei pazienti e la correlazione tra campioni accoppiati di plasma e DBS. L'applicazione di adeguate analisi statistiche per lo studio di cross-validazione ha mostrato l'assenza di una forte correlazione tra le concentrazioni plasmatiche e quelle in DBS ed ha suggerito di aumentare il numero di pazienti e di rivalutare l'effetto dell'ematocrito e del volume dello spot per migliorare tale conversione.
Sono stati sviluppati altri due metodi LC-MS/MS per la quantificazione di LENVA sia nel plasma umano sia nel DBS utilizzando due diverse carte da filtro (Whatman 31 ET CHR e Whatman 903). Questi metodi sono stati validati secondo le linee guida di riferimento di EMA, FDA e per il DBS. Il metodo basato sul plasma ha un ampio range analitico (0,5-2000 ng/mL) ed è stato applicato per quantificare 24 campioni di plasma ottenuti da 6 pazienti trattati con LENVA e arruolati nello studio CRO-2018-83. Il corrispondente metodo basato su DBS ha un range analitico leggermente ridotto (5-2000 ng/mL) ed è stato applicato per l'analisi di 4 campioni di pazienti DBS. Non sono stati ancora condotti studi di correlazione a causa della scarsità di campioni dei pazienti raccolti fino ad ora.
L'applicazione di questi metodi analitici agli studi in corso presso il CRO di Aviano consentirebbe di raccogliere dati utili per approfondire le conoscenze sulla possibile correlazione tra i livelli plasmatici e l'esito del trattamento o tossicità<br>Therapeutic Drug Monitoring (TDM) is the clinical practice of measuring a specific drug at defined intervals of time to maintain plasma concentrations within a targeted therapeutic window, to maximize efficacy and minimize toxicity. Robust, sensitive, and reproducible analytical methods to quantify anticancer drugs in biological fluids are needed to make this approach feasible. This PhD project focused on four different oral anticancer drugs used to treat patients with advanced HCC: sorafenib (SORA), regorafenib (REGO), lenvatinib (LENVA), and idarubicin (IDA), whose safety and efficacy as a third-line therapy option is currently under investigation.
SORA, REGO, and LENVA were also involved in a cross-validation study (CRO-2018-83) ongoing at Centro di Riferimento Oncologico di Aviano (CRO), where the primary aim was the cross-validation between the plasma-based LC-MS/MS method and the Dried Blood Spot (DBS)-based LC-MS/MS assay to demonstrate that DBS can be used alternatively to plasma sample to quantify these drugs. DBS may improve TDM applicability thanks to its more patient-friendly procedures for sample collection. Instead, the quantification of IDA and its active metabolite (idarubicinol) in human plasma was required as a secondary aim of a phase II clinical study (CRO-2017-42) ongoing at CRO.
For all these drugs, exposure-response and -toxicity data are still limited or lacking, thus highlighting the necessity of deepening this type of investigation.
To assess drug plasma concentration in biological matrices, reliable analytical methods are needed.
In this contest, two LC-MS/MS methods were developed and validated according to international guidelines to simultaneously quantify SORA, REGO, and 3 active metabolites (SORA N oxide, REGO N oxide, and N desmethyl REGO N oxide), both in human plasma and DBS. These methods have the same analytical range (50-8000 ng/mL) for SORA and REGO and (30-4000 ng/mL) for the metabolites. After the validations, these methods were applied to quantify 66 plasma samples and 63 DBS obtained from 16 patients, treated with SORA or REGO and enrolled in CRO 2018 83. This analysis allowed to obtain preliminary data regarding the concentrations of the drugs in patients and the correlation between plasma and DBS paired samples the application of proper statistical analyses for the cross-validation study showed the absence of a strong correlation between plasma and DBS concentrations and it suggested to enlarge patients number and to re-evaluate Hct and spot-volume effect to enhance the DBS-to-plasma conversion performance.
Two additional LC-MS/MS methods were developed for the quantification of LENVA both in human plasma and DBS using two different filter papers (Whatman 31 ET CHR and Whatman 903). These methods were validated according to EMA, FDA, and DBS references guidelines. The plasma-based method has a wide analytical range (0.5-2000 ng/mL) and it was applied to quantify 24 plasma samples obtained from 6 patients treated with LENVA and enrolled in CRO-2018-83. The corresponding DBS-based method has a slightly reduced analytical range (5-2000 ng/mL) and it was applied for the analysis of 4 DBS patients’ samples. No correlation studies have yet been performed due to the paucity of patients’ samples collected till now.
The application of these analytical methods to the ongoing studies at the C.R.O. di Aviano should allow to collect useful data to deepen the knowledge about the possibility of establishing a correlation between drug exposure levels and patients’ outcome or toxicity development. The aim is to implement the application of TDM for these anticancer drugs in clinical practice.
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Mao, Söderberg Mao. "Clinical Pharmacogenetics of Olanzapine : with Focus on FMO Gene Polymorphisms." Doctoral thesis, Uppsala universitet, Klinisk farmakogenomik och osteoporos, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-179957.
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Pharmacogenetics is the study of variability in drug response attributed to genetic variation. Olanzapine (OLA) is a widely used antipsychotic drug for schizophrenia treatment. The pharmacokinetics of OLA display large inter-individual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need of individualized dosing in order to avoid concentration-dependent adverse effects and therapeutic failure. The observed variability has been partially explained by environmental and physiological factors. Genetically determined differences in drug metabolism represent a less studied source of variability. Precluded contribution by cytochrome P450 (CYP) 2D6 calls for evaluation of the other major OLA metabolizing enzymes. The objective of this thesis was to study pharmacogenetic influence of flavin-containing monooxygenase (FMO) 1 and 3, CYP1A2 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4 on therapeutic OLA exposure. We conducted genetic association studies applying gene re-sequencing and genotyping of candidate and tagging SNPs. Patients carrying the FMO1*6 allele displayed increased dose-adjusted concentrations (C/Ds) of OLA, in serum as well as cerebrospinal fluid. Patients who were homozygous for the FMO3 K158-G308 compound variant showed reduced C/Ds of OLA N-oxide metabolite, but no alteration in OLA exposure. This compound variant is expected to have clinical relevance primarily for non-African populations, since low frequencies were detected among native Africans. Deviation in OLA exposure was observed in carrier of a rare FMO3 mutation, predicted in silico to affect gene splicing. Reduced OLA exposure was observed in UGT1A4*3 carriers. The CYP1A2 -163(A) (CYP1A2*1F) variant was not associated with increase in CYP1A2-catalyzed OLA metabolism or reduction in OLA exposure. Correlations were detected for two cis-acting variants within the inter-genetic region of the CYP1A cluster and a trans-acting variant located upstream the locus encoding aryl hydrocarbon receptor. The inconsistent data reported for CYP1A2*1F could be explained by presence of ethnic specific haplotype structures incorporating the -163(A) variant. A continuously improved understanding of the wide range of factors that can influence pharmacokinetics and pharmacodynamics will increase the likelihood of achieving optimal treatment response for individual patients.
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Mercolini, Laura <1979>. "Development of original analytical methods for the therapeutic drug monitoring of CNS druges: Antipsychotics, Antidepressants and Anxiolytics-hypnotics." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2713/1/mercolini_laura_tesi.pdf.
Full textAbstract:
Great strides have been made in the last few years in the pharmacological treatment of neuropsychiatric disorders, with the introduction into the therapy of several new and more efficient agents, which have improved the quality of life of many patients. Despite these advances, a large percentage of patients is still considered “non-responder” to the therapy, not drawing any benefits from it. Moreover, these patients have a peculiar therapeutic profile, due to the very frequent application of polypharmacy, attempting to obtain satisfactory remission of the multiple aspects of psychiatric syndromes. Therapy is heavily individualised and switching from one therapeutic agent to another is quite frequent. One of the main problems of this situation is the possibility of unwanted or unexpected pharmacological interactions, which can occur both during polypharmacy and during switching. Simultaneous administration of psychiatric drugs can easily lead to interactions if one of the administered compounds influences the metabolism of the others. Impaired CYP450 function due to inhibition of the enzyme is frequent. Other metabolic pathways, such as glucuronidation, can also be influenced. The Therapeutic Drug Monitoring (TDM) of psychotropic drugs is an important tool for treatment personalisation and optimisation. It deals with the determination of parent drugs and metabolites plasma levels, in order to monitor them over time and to compare these findings with clinical data. This allows establishing chemical-clinical correlations (such as those between administered dose and therapeutic and side effects), which are essential to obtain the maximum therapeutic efficacy, while minimising side and toxic effects.
It is evident the importance of developing sensitive and selective analytical methods for the determination of the administered drugs and their main metabolites, in order to obtain reliable data that can correctly support clinical decisions. During the three years of Ph.D. program, some analytical methods based on HPLC have been developed, validated and successfully applied to the TDM of psychiatric patients undergoing treatment with drugs belonging to following classes: antipsychotics, antidepressants and anxiolytic-hypnotics. The biological matrices which have been processed were: blood, plasma, serum, saliva, urine, hair and rat brain. Among antipsychotics, both atypical and classical agents have been considered, such as haloperidol, chlorpromazine, clotiapine, loxapine, risperidone (and 9-hydroxyrisperidone), clozapine (as well as N-desmethylclozapine and clozapine N-oxide) and quetiapine. While the need for an accurate TDM of schizophrenic patients is being increasingly recognized by psychiatrists, only in the last few years the same attention is being paid to the TDM of depressed patients. This is leading to the acknowledgment that depression pharmacotherapy can greatly benefit from the accurate application of TDM. For this reason, the research activity has also been focused on first and second-generation antidepressant agents, like triciclic antidepressants, trazodone and m-chlorophenylpiperazine (m-cpp), paroxetine and its three main metabolites, venlafaxine and its active metabolite, and the most recent antidepressant introduced into the market, duloxetine. Among anxiolytics-hypnotics, benzodiazepines are very often involved in the pharmacotherapy of depression for the relief of anxious components; for this reason, it is useful to monitor these drugs, especially in cases of polypharmacy. The results obtained during these three years of Ph.D. program are reliable and the developed HPLC methods are suitable for the qualitative and quantitative determination of CNS drugs in biological fluids for TDM purposes.
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Mercolini, Laura <1979>. "Development of original analytical methods for the therapeutic drug monitoring of CNS druges: Antipsychotics, Antidepressants and Anxiolytics-hypnotics." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2713/.
Full textAbstract:
Great strides have been made in the last few years in the pharmacological treatment of neuropsychiatric disorders, with the introduction into the therapy of several new and more efficient agents, which have improved the quality of life of many patients. Despite these advances, a large percentage of patients is still considered “non-responder” to the therapy, not drawing any benefits from it. Moreover, these patients have a peculiar therapeutic profile, due to the very frequent application of polypharmacy, attempting to obtain satisfactory remission of the multiple aspects of psychiatric syndromes. Therapy is heavily individualised and switching from one therapeutic agent to another is quite frequent. One of the main problems of this situation is the possibility of unwanted or unexpected pharmacological interactions, which can occur both during polypharmacy and during switching. Simultaneous administration of psychiatric drugs can easily lead to interactions if one of the administered compounds influences the metabolism of the others. Impaired CYP450 function due to inhibition of the enzyme is frequent. Other metabolic pathways, such as glucuronidation, can also be influenced. The Therapeutic Drug Monitoring (TDM) of psychotropic drugs is an important tool for treatment personalisation and optimisation. It deals with the determination of parent drugs and metabolites plasma levels, in order to monitor them over time and to compare these findings with clinical data. This allows establishing chemical-clinical correlations (such as those between administered dose and therapeutic and side effects), which are essential to obtain the maximum therapeutic efficacy, while minimising side and toxic effects.
It is evident the importance of developing sensitive and selective analytical methods for the determination of the administered drugs and their main metabolites, in order to obtain reliable data that can correctly support clinical decisions. During the three years of Ph.D. program, some analytical methods based on HPLC have been developed, validated and successfully applied to the TDM of psychiatric patients undergoing treatment with drugs belonging to following classes: antipsychotics, antidepressants and anxiolytic-hypnotics. The biological matrices which have been processed were: blood, plasma, serum, saliva, urine, hair and rat brain. Among antipsychotics, both atypical and classical agents have been considered, such as haloperidol, chlorpromazine, clotiapine, loxapine, risperidone (and 9-hydroxyrisperidone), clozapine (as well as N-desmethylclozapine and clozapine N-oxide) and quetiapine. While the need for an accurate TDM of schizophrenic patients is being increasingly recognized by psychiatrists, only in the last few years the same attention is being paid to the TDM of depressed patients. This is leading to the acknowledgment that depression pharmacotherapy can greatly benefit from the accurate application of TDM. For this reason, the research activity has also been focused on first and second-generation antidepressant agents, like triciclic antidepressants, trazodone and m-chlorophenylpiperazine (m-cpp), paroxetine and its three main metabolites, venlafaxine and its active metabolite, and the most recent antidepressant introduced into the market, duloxetine. Among anxiolytics-hypnotics, benzodiazepines are very often involved in the pharmacotherapy of depression for the relief of anxious components; for this reason, it is useful to monitor these drugs, especially in cases of polypharmacy. The results obtained during these three years of Ph.D. program are reliable and the developed HPLC methods are suitable for the qualitative and quantitative determination of CNS drugs in biological fluids for TDM purposes.
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AIASSA, SIMONE. "Smart Electronic Pen for Continuous Monitoring of Anaesthetics." Doctoral thesis, Politecnico di Torino, 2021. http://hdl.handle.net/11583/2942124.
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Mitrev, Nikola. "Therapeutic drug monitoring guided anti-tumour necrosis factor therapy in inflammatory bowel disease (IBD): Gastroenterological Society of Australia (GESA)/ Australian IBD Association (AIBDA) consensus statements." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17449.
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INTRODUCTION: Growing evidence supports the use of therapeutic drug monitoring (TDM) to guide anti-tumour necrosis factor (TNF) drug treatment among patients with inflammatory bowel disease (IBD). Currently, TDM for anti-TNF drugs is variably practiced by gastroenterologists in Australia. Our aim was to develop consensus statements for TDM of anti-TNF drugs in IBD that will be endorsed by the Australian IBD Association (AIBDA) of the Gastroenterological Society of Australia (GESA). METHODS: A consensus committee of 25 Australian and international experts was assembled. A systematic literature search aided the steering committee in developing the initial draft statements. A modified Delphi technique was used with three iterations, with modification of statements based on feedback and anonymous voting. Statements with 80% agreement without reservation or only minor reservation in the third voting round were accepted as consensus. RESULTS: 22/24 statements met criteria for consensus. The committee agreed that TDM for anti-TNF agents should be performed upon treatment failure, following successful induction, when contemplating a drug-holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 μg/mL and 5-12 μg/mL, respectively, were determined as appropriate. The therapeutic range may need to be altered for different disease phenotypes or treatment endpoints. In treatment failure, TDM may identify mechanisms to guide subsequent decisionmaking. Among patients in remission, TDM-guided anti-TNF drug dose optimisation may reduce treatment cost and avoid future relapse. Data indicates drug-tolerant antidrug antibody assays do not offer an advantage over drug-sensitive assays in 7 predicting outcomes. Further data are required prior to recommending TDM for nonanti- TNF biologics. CONCLUSION: These consensus statements are expected to aid use of TDM by gastroenterologists in Australia and abroad to guide anti-TNF drug treatment in IBD patients.
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Baldoni, André de Oliveira. "Epilepsia Refratária e Lamotrigina: Monitorização terapêutica e resposta clínica em pacientes ambulatoriais." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/60/60137/tde-27092013-141728/.
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Introdução: O tratamento farmacológico é primeira opção para o tratamento da epilepsia, e cerca de 40% dos pacientes não respondem à monoterapia e, sendo necessário o uso de dois ou mais fármacos antiepilépticos (FAE) para o melhor controle das crises epilépticas. Nesta situação clínica a lamotrigina (LTG) é o FAE de segunda geração com maior prevalência de uso, em associação com os demais FAE. Objetivo: Analisar o perfil sociodemográfico, farmacoepidemiológico, clínico e laboratorial dos pacientes com epilepsia refratária em uso de LTG, bem como verificar a racionalidade da monitorização terapêutica da LTG. Casuística e Método: Este estudo de caráter observacional e transversal foi realizado com 75 pacientes com epilepsia refratária em uso de LTG atendidos no Ambulatório de Epilepsia de Difícil Controle (AEDC) do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), no período de maio/2011 a abril/2012. As variáveis clínicas analisadas foram a qualidade de vida (Quality of Life in Epilepsy - Qolie-31), o perfil de eventos adversos (AEP - Adverse Events Profile) e a adesão ao tratamento medicamentoso (Morisky- Green). Os dados sociodemográficos e farmacoterapêuticos foram coletados através dos prontuários médicos. Além disso, foi realizada a dosagem da concentração plasmática da LTG e dos FAE de primeira geração. Para testar as hipóteses o nível de significância foi fixado em ? = 0,05, e intervalo de confiança de 95%. O trabalho foi aprovado pelo Comitê de Ética em Pesquisa do HCFMRP (no 8791/2010). Resultados e Discussão: Identificou-se elevada prevalência de uso de politerapia (97%), 29% dos pacientes apresentaram concentrações plasmáticas de LTG abaixo do intervalo de referência preconizado (< 2,5 mg/L), 45% utilizaram doses mg/kg/dia abaixo do recomendado, e 60% apresentaram comprometimento com a adesão ao tratamento medicamentoso. Os FAE de primeira geração influenciaram de forma significativa a concentração plasmática de LTG (p< 0,01). A concentração plasmática de LTG apresentou associação com a dose (mg/kg/dia) utilizada pelos pacientes (p = 0,0096). Os eventos adversos mais prevalentes foram sonolência e dificuldade de concentração. Baixos escores foram observados em todos os domínios relacionados à qualidade de vida (Qolie-31), sugerindo comprometimento significativo desse parâmetro humanístico entre os pacientes com epilepsia refratária. A qualidade de vida apresentou associação inversamente significativa com os eventos adversos obtidos pelo AEP (r = -0.69, p<0.01). Conclusão: Os pacientes com epilepsia refratária em uso de LTG apresentaram elevada prevalência de problemas clínicos, humanísticos e farmacoterapêuticos, o que demonstra a necessidade de implementação de estratégias para otimização do tratamento farmacológico, tais como, implementação efetiva e permanente da monitorização terapêutica de LTG nos serviços de saúde.<br>Introduction: The pharmacological treatment is the first choice for the treatment of epilepsy and about 40% of patients are not responding to monotherapy. Therefore these require two or more antiepileptic drugs (AED) for better control of seizures. In this clinical situation, lamotrigine (LTG) is the AED of second generation most used in combination with other AED. Objective: To analyze the demographic, pharmacoepidemiological, clinical and laboratorial profile of patients with refractory epilepsy using LTG, as well as, to analyze the rationality of LTG therapeutic monitoring. Casuist and Methods: This observational and cross-sectional study was conducted on 75 adult outpatients with refractory epilepsy in use of LTG attended at the Ambulatory of epilepsy difficult to control (AEDC) of the Ribeirão Preto Medical School University Hospital (HCFMRP-USP). The patients were invited between May 2011 to April 2012. The clinical variables analyzed by questionnaire were quality of life (Quality of Life in Epilepsy - QOLIE-31), adverse event profile (AEP - Adverse Events Profile) and medication adherence (Morisky-Green). The sociodemographic and pharmacotherapeutic variables were collected through medical records. In addition, it was performed plasma concentration of LTG and of the first generation AED. To test the hypotheses the significance level was set at ? = 0.05, and a confidence interval of 95%. The study was approved by the Research Ethics Committee of HCFMRP-USP. Results and Discussion: It was observed high prevalence of use of polytherapy (97%), 29% of patients had LTG plasma concentrations below the recommended reference range (<2.5 mg / L), 45% used doses mg/kg/day lower than recommended, and 60% were not adherent to medication. The first generation AED influenced significantly in the LTG plasma concentration (p <0.01). The LTG dose (mg/kg/day) used by patients presented positive association with LTG plasma concentration (p = 0.0096). The most prevalent adverse events were somnolence and difficulty concentrating. Low scores were observed in all subscales related to quality of life (QOLIE-31), suggesting significant harm of this humanistic parameter among patients with refractory epilepsy. The quality of life was associated inversely with adverse events obtained by AEP (r = - 0.69, p <0:01). Conclusion: Patients with refractory epilepsy using LTG had high prevalence of clinical, humanistic and pharmacotherapeutic problems, which demonstrates the need to implement strategies for optimization of pharmacological treatment, such as, implementation of permanent and effective therapeutic monitoring of LTG in health services.
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Marques, Fabiana Angelo. "Monitorização terapêutica do topiramato em pacientes com epilepsia refratária." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/60/60137/tde-01072015-094425/.
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A estratégia mais amplamente utilizada no tratamento da epilepsia é a farmacoterapia. Entretanto cerca de 30% dos pacientes mesmo utilizando o fármaco adequado para o seu diagnóstico não respondem ao tratamento proposto, sendo então diagnosticados com epilepsia refratária. Entre as drogas antiepilépticas (DAE) utilizadas no tratamento da epilepsia refratária encontra-se o topiramato (TPM). O objetivo do presente estudo foi avaliar a concentração plasmática (Cp) do TPM verificando a influência da dose prescrita (mg/Kg/dia), sexo, idade e o uso de outras DAE sobre a mesma, correlacionando-a com a frequência de crises epilépticas, reações adversas, qualidade de vida e adesão a farmacoterapia. Este estudo observacional transversal foi realizado com 37 pacientes com epilepsia refratária em uso de TPM atendidos no Ambulatório de Epilepsia de Difícil Controle do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. As variáveis de interesse foram qualidade de vida (Quality of Life in Epilepsy - QOLIE-31), reações adversas ao medicamento (RAM) (Liverpool Adverse Event Profile - LAEP), adesão a farmacoterapia (Modified Morisky Scale - MMS), tipo de crise epiléptica, tipo de epilepsia, frequência das crises, características farmacoterapêuticas e sociodemográficas, obtidas por meio de instrumentos na entrevista com o paciente ou em prontuário. Além disso, amostras de sangue de todos os participantes foram coletadas para dosagem da Cp de TPM, lamotrigina e DAEs de primeira geração em uso. O trabalho foi aprovado pelo Comitê de Ética em Pesquisa da Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP (nº 030/2014). A idade média dos pacientes foi 40 anos (DP 10,7) e apresentavam prevalentemente epilepsia focal sintomática (73,0%) e crises parciais complexas (67,6%). Em relação ao perfil farmacoterapêutico, 97,3% dos pacientes estavam em politerapia, sendo o esquema farmacoterapêutico mais prevalente a associação entre TPM, carbamazepina e clobazam (29,8%). A Cp de 83,8% dos pacientes em uso de TPM encontraram-se abaixo do intervalo de referência recomendado (5,0 -20,0 mg/L), sendo a Cp média de 3,21 mg/L (DP 2,76). A dose prescrita (mg/Kg/dia) e o uso concomitante de indutores do metabolismo do TPM explicaram 69,0% da variabilidade da Cp do TPM: estimou-se que o aumento na dose de 1,0 mg/Kg/dia tenha promovido o aumento de 0,68 mg/L na Cp do TPM, enquanto o uso de indutores esteve relacionado a uma redução de 2,97 mg/L (p?0,001). Os pacientes com Cp < 5,0 mg/L apresentaram o número médio de crises epilépticas maior do que aqueles com Cp no intervalo de referência (p<0,001). A pontuação média do LAEP foi de 40,5 (DP 10,1) e a sonolência, problemas de memória e o nervosismo e/ou agressividade foram as reações adversas mais prevalentes. Com relação à qualidade de vida o escore médio obtido no QOLIE-31 foi de 47,7 (DP 15,2), sendo que a preocupação com as crises e a função social foram os domínios que apresentaram maior comprometimento na qualidade de vida dos pacientes. Ademais, foram encontradas evidências de uma relação inversa entre RAM e a qualidade de vida, sendo que o aumento de um ponto no escore do LAEP reduz o escore do QOLIE-31 em 0,91 pontos. Finalmente, segundo resultados do MMS, 62,2% dos pacientes eram aderentes ao tratamento medicamentoso. Em conclusão a dose prescrita e o uso de DAE indutoras do metabolismo do TPM influenciaram a Cp deste fármaco, a qual afetou o controle das crises epilépticas. Diante disto sugere-se a monitorização terapêutica como uma ferramenta para a otimização da farmacoterapia e da resposta clínica.<br>The most widely used strategy in epilepsy treatment is pharmacotherapy. However, near 30% of all patients, even though receiving the appropriate drug, do not respond to recommended treatment. Among the antiepileptic drugs (AED) used for the treatment of refractory epilepsy there is topiramate (TPM). The aim of this study was to evaluate TPM\'s plasma concentration (Cp) and to verify the influence of some variables [prescribed dose (mg/Kg/day), sex, age and other AED in use] on it, as well as correlate TPM\'s Cp with the frequency of epileptic crises, adverse events, quality of life and adherence to pharmacotherapy. This cross-sectional study enrolled 37 patients diagnosed with refractory epilepsy in use of TPM attended at the Epilepsy of Difficult Control\'s ambulatory of the Ribeirão Preto Medical School University Hospital. The investigated variables were quality of life (Quality of Life in Epilepsy - QOLIE-31), adverse drug reactions (ADR) (Liverpool Adverse Event Profile - LAEP), adherence to pharmacotherapy (Modified Morisky Scale - MMS), type of epileptic crisis, type of epilepsy, frequency of crises, pharmacotherapeutic and sociodemographic characteristics, all of them obtained through medical records and/or face to face interview. Moreover, blood samples of all patients were collected in order to measure Cp of TPM, lamotrigine and first generation AEDs in use. The study was approved by the Research Ethics Committee of the School of Pharmaceutical Sciences of Ribeirão Preto-USP (nº 030/2014). The patients\' mean age was 40 years (SD 10.7) and they showed predominantly symptomatic focal epilepsy (73.0%) and partial complex seizures (67.6%). Considering the pharmacotherapeutic profile, 97.3% of them were under polytherapy, in which the most prevalent regimen consisted in the combination of TPM, carbamazepine and clobazam (29.8%). From all patients in use of TPM, the mean Cp for this drug was 3.21 mg/L (SD 2.76) and 83.8% presented values below the recommended reference range (5.0 mg/L). The prescribed dose (mg/Kg/day) and concomitant use of TPM\'s metabolism inducers explained 69.0% of TPM\'s Cp variability: it was estimated that an increment of 1.0 mg/Kg/day in the dosage of TPM has lead to an increase of 0.68 mg/L in its Cp, while the use of inducers was related to a decrease of 2.97 mg/L (p?0.001). Patients with Cp < 5.0 mg/L showed a larger mean number of crises than those whose Cp was within the reference range (p<0.001). The LAEP\'s mean score was 40.5 (SD 10.1) and somnolence, memory problems and nervousness and/or agitation were the most common adverse events. Regarding quality of life, QOLIE-31\'s mean score was 47.7 (SD 15.2), wherein concern about the crisis and social role were the areas related to greater impairment in patients\' quality of life. Furthermore, we found evidences of an inverse relationship between ADR and quality of life in which the one point increase in LAEP score reduced QOLIE-31 score in 0.91 point. Finally, according to MMS results, 62.2% of patients were adherent to their treatment. In conclusion prescribed dose and concomitant use of AEDs that induced TPM\'s metabolism influenced on this drug\'s Cp, which seemed to affect epileptic seizures control. Thus, we suggest the use of therapeutic drug monitoring of TPM as a tool for pharmacotherapy optimization so as to improve the clinical response in these patients.
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Best, Emma Women's & Children's Health Faculty of Medicine UNSW. "Once daily gentamicin in infants and children: an evaluation of safety and the role of therapeutic drug monitoring in minimising toxicity." Awarded by:University of New South Wales, 2007. http://handle.unsw.edu.au/1959.4/35192.
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AIMS: To assess (i) the safety of once daily dosing (ODD) of gentamicin by systematic evaluation of ototoxicity and nephrotoxicity; and (ii) the usefulness of therapeutic drug monitoring (TDM) in a paediatric cohort. METHOD: Infants and children with suspected or proven gram negative sepsis were enrolled prospectively to receive ODD gentamicin at 7 mg/kg/day. Neonates were excluded. Hearing and renal function were assessed at baseline, during and after therapy by otoacoustic emissions (OAE) and by either serum creatinine or glomerular filtration rate. Abnormal OAE were followed with audiometry. TDM was performed using an interval adjusted graphical method (Hartford nomogram) with levels taken between 6-14 hours after dose. Assessment of efficacy (clinical and microbiological) was a secondary outcome measure. RESULTS: There were 106 episodes of therapy in 79 children (median age 5.6 years; range 1 month - 16 years), 60% of which were for febrile neutropaenia. Evaluation was complete in 88% (93/106) for ototoxicity and 92% (98/106) for nephrotoxicity. Two children (1.88%, 95% CI 0.10 - 7.13) experienced permanent hearing loss. Three children did not complete full assessment after preliminary abnormalities on OAE. Incorporating these cases gives a ???worst case scenario??? incidence of 4.71% (95% CI 1.71 - 10.91) possible ototoxicity. One child (0.94%, 95% CI < 0.10 - 5.73) experienced transient nephrotoxicity. No ???toxic??? serum gentamicin levels were detected, including in those children who experienced clinical toxicity. All children with detectable toxicity were undergoing treatment for malignancies and had received nephro or ototoxic medications prior to the gentamicin course. Complete or partial efficacy was seen in 93% (non oncology) and 78% (oncology) treatment episodes, equivalent to prior literature reports. CONCLUSION: In this systematically evaluated paediatric cohort receiving ODD gentamicin, toxicity occurred infrequently and only in those with identifiable risk factors. TDM did not identify children who developed clinical toxicity. The development of toxicity appears to be associated with factors such as underlying medical condition, prior courses of gentamicin, exposure to other oto or nephrotoxic medications, all of which may be more predictive of toxicity than elevated serum gentamicin levels. TDM in healthy children on short course gentamicin appears unnecessary, but may be warranted in conjunction with renal and hearing assessments in those with risk factors.
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Ahmed, Omar. "Contribution of capillary electrophoresis for the therapeutic drug monitoring of patients treated by targeted cancer therapy : application to tyrosine kinase Inhibitors." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTS148.
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L'objectif de ce travail de thèse était d’évaluer l’apport de l'électrophorèse capillaire (EC) comme technique analytique pour la quantification des inhibiteurs de la tyrosine kinase (ITKs) présents dans des échantillons plasmatiques humains dans le contexte du STP. 4 ITKs ont été sélectionnés pour cette étude: mesylate d’imatinib, chlorhydrate d’erlotinib, ditosylate de lapatinib et sorafenib. Tout d’abord, une méthode simple, rapide et peu couteuse a été développée par électrophorèse capillaire de zone (CZE) avec détection UV. Cette méthode reposait sur l’utilisation d’une méthode de préparation d’échantillon par précipitation des protéines à l’ACN avant l’analyse par CZE-UV. Une étude approfondie a également été réalisée pour comprendre le comportement électrophorétique de l’imatinib en présence de sels et d’ACN dans l’échantillon plasmatique. Ensuite, une seconde étude a été réalisée pour optimiser une méthode de préparation d’échantillon simple, rapide et efficace basée sur le principe d’extraction liquide-liquide en présence de sel (SALLE). Cette méthode SALLE reposait sur l’ajout de sels en grande concentration dans deux solvants immiscibles permettant ainsi d’extraire en une seule étape les ITKs du plasma vers la phase ACN avec des rendements d’extraction élevés. Les extraits étaient ensuite analysés directement par CZE-UV. L’utilisation de l’ACN comme solvant d’extraction permettait d’injecter des volumes d’échantillon allant jusqu’à 80% du volume effectif du capillaire. Les ITKs étaient donc concentrés en tête du capillaire grâce à l’existence de mécanisme de préconcentration électrophorétiques. Dans la perspective d'une utilisation en routine, la méthodologie SALLE-CZE-UV a été entièrement automatisée. Les performances analytiques obtenues pour les quatre ITKs sont parfaitement adaptées aux exigences du STP. Enfin, la méthode SALLE-CZE-UV a été appliquée avec succès pour l'extraction et l'analyse des quatre ITKs directement à partir de sang humain. Tous les développements actuels prouvent que la CE est une technique pertinente pour résoudre de nombreux problèmes rencontrés dans le contexte du STP<br>The objective of the present work was to evaluate the relevance of capillary electrophoresis (CE) method for the quantification of tyrosine kinase inhibitors (TKIs) in human plasma in the context of TDM. Four TKIs were selected for this study: imatinib mesylate, erlotinib hydrochloride, lapatinib ditosylate and sorafenib.A fast, simple and cost effective CZE-UV methodology for the quantification of imatinib in plasma was first developed using simply ACN precipitation as sample preparation before analysis. A complete study was performed to understand the electrophoretic behavior of imatinib in the presence of salt (from plasma) and ACN in the sample matrix. Then, a thorough study was performed to optimize an easy to use and performing sample pretreatment methodology based on salting-out assisted liquid-liquid extraction (SALLE) for the four TKIs from human plasma. SALLE, which is based on adding high concentration of salt to two miscible liquids, allows to extract in one step TKIs from plasma in an ACN phase with high recovery. The extracted TKIs can then be directly injected for further CZE-UV analysis. The use of ACN as extraction solvent allows to inject up to 80% of the capillary effective volumes. This allows in-line sample concentration through electrophoretic stacking mechanisms. In the perspective of routine use, the SALLE-CZE-UV methodology was fully automated. The analytical performances obtained for the four TKIs are fully suitable with TDM requirements. Finally, the SALLE-CZE-UV was successfully applied for the extraction and analysis of the four TKIs directly from human blood. All the present developments prove that CE is a relevant technique to address many TDM issues
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Al, Hawaj Maitham. "Therapeutic Drug Monitoring of Factor VIII Prophylaxis Using Its Plasma Coagulant Activity and Global Hemostasis Biomarkers: A Pharmacokinetic/Pharmacodynamic Pilot Study." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/2756.
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Background: The current clinical practice of factor VIII (FVIII) prophylaxis revolves around converting patients with severe hemophilia A, hereafter simply referred to as hemophilia, phenotype (defined as plasma factor VIII coagulant activity [FVIII:C] <1 IU dL-1) to moderate hemophilia phenotype (defined as plasma FVIII:C from 1–5 IU dL-1). However, a wide inter-individual variation in bleeding tendency is observed despite changes in plasma FVIII:C (pharmacokinetic [PK] changes). Therefore, monitoring FVIII prophylaxis by global hemostasis biomarkers (pharmacodynamic [PD] response) can potentially be beneficial. Objective: To conduct appropriate PK/PD modeling using plasma FVIII:C and global hemostasis (platelet function and blood viscoelastic) biomarkers in severe hemophilia. Methods: Nine non-bleeding severe hemophiliacs (plasma FVIII:C <1 IU dL-1) with variant bleeding tendency (5 frequent bleeders and 4 infrequent bleeders) were infused with a recombinant factor FVIII (rFVIII) prophylactic dose (mean = 32.1 international units per kilogram [IU kg-1]). Blood was collected at baseline and 0.5-, 1-, 2-, 4-, 8-, 12-, 24- and 48-hours (h) post-dose for plasma FVIII:C, platelet function (platelet contractile force [PCF], clot elastic modulus [CEM] and force onset time [FOT]) and blood viscoelastic (reaction-time [R], kinetics-time [K] and maximum amplitude [MA]) biomarkers and activated partial thromboplastin time (aPTT). Non-compartmental analysis (NCA) was performed using standard methods. Compartmental analysis (CA) and PK/PD modeling were performed by non-linear regression. Correlation and analysis of variance (ANOVA) were used to explore the role of clinically relevant modifiers of bleeding tendency, as appropriate. ANOVA was used to assess inter-group differences in pertinent PK and PD parameters. P value <0.05 significance level was pre-specified for all statistical tests. Results: Mean (±SD) volume of distribution at steady state (Vss), total clearance (CLtot) and terminal half-life (t1/2) from NCA were 40.5 (±11.2) milliliter per kilogram (mL kg-1), 2.9 (±1.2) milliliter per hour per kilogram (mL h-1 kg-1) and 11.6 (±6.2) h, respectively. Mean (±SD) Vss and CLtot from the one-compartment body model (CA) were 39.6 (±8.9) mL kg-1 and 3.1 (±1.3) mL h-1 kg-1, respectively. The mean (±SD) baseline effect (E0) and slope from the PK/PD linear modeling were: for aPTT, 48.9 (±4.4) seconds (sec) and -0.025 (±0.009) second deciliter per international unit (sec dL IU-1), respectively; for PCF, 0.3 (±0.3) kilodynes (kdynes) and 0.008 (±0.004) kilodynes deciliter per international unit (kdynes dL IU-1), respectively; and for CEM, 0.0 (±0.0) kilodynes per square centimeter (kdynes cm-2) and 0.032 (±0.016) kilodynes deciliter per international unit per square centimeter (kdynes dL IU-1 cm-2), respectively. The mean (±SD) maximum effect (Emax) and half the maximum effective concentration (EC50) from the PK/PD sigmoidal Emax model were: for FOT, 70.1 (±16.9) % reduction and 87.8 (±31.4) IU dL-1 for FOT, respectively; for R, 74.9 (±26.0) % reduction and 68.5 (±28.4) IU dL-1, respectively; and for K, 73.2 (±36.4) % reduction and 67.2 (±29.0) IU dL-1, respectively. MA was not PK/PD modeled due to its low sensitivity. Conclusions: Plasma FVIII:C remained ≥1 IU dL-1 over the prophylactic interval. FOT and R were the most sensitive biomarkers at lower plasma FVIII:C. PCF and CEM were more sensitive than K and aPTT at lower plasma FVIII:C. MA was the least sensitive biomarker. Correlation and inter-group differences did not reach statistical significance (small sample size). These results may be used to assess risk of bleeding and dose-optimize FVIII prophylaxis in severe hemophilia.
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Gerard, Cécile. "Apport des modèles PBPK dans l'optimisation thérapeutique des inhibiteurs des calcineurines en transplantation." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10265/document.
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En transplantation d'organes solides ou en greffe de moelle osseuse, la ciclosporine et letacrolimus ont prouvé leur efficacité. Ils sont cependant de maniement délicat du fait d'unintervalle thérapeutique étroit et d'une grande variabilité pharmacocinétique inter et intraindividuelle.Un suivi thérapeutique et une adaptation des posologies de ces médicaments sontnécessaires pour diminuer le risque de rejet et limiter leur toxicité.Un modèle PBPK est construit à partir de considérations anatomiques, physiologiques etbiochimiques. Il permet d'apporter des informations sur les cinétiques tissulaires et sur lesrépercussions des altérations physiologiques ou pathologiques.Les modalités optimales d'administration de la ciclosporine en greffe de moelle osseusepédiatrique, ainsi que les zones thérapeutiques à atteindre, font l'objet de débats. Un modèlePBPK-PD pour la ciclosporine construit à partir de données chez le rat puis extrapolé etvalidé chez l'homme a permis d'estimer l'exposition à la ciclosporine dans les organes ciblesde la GVH, de comparer les modalités d'administration en perfusion intraveineuse, et dedéfinir des concentrations cibles en fonction des indications. L'adaptation posologique du tacrolimus en transplantation hépatique par la méthodeBayésienne reste relativement imprécise dans la période initiale après la greffe, parce que lesfacteurs de variabilité sont imparfaitement connus. Un modèle PBPK a été construit et évaluéafin de rechercher les covariables pertinentes par une approche bottom-up : la fonctionhépatique, l'hématocrite, le génotype du cytochrome P450 3A5 du donneur, la fraction libre etcertaines comédications ont été retrouvées<br>In solid organ or bone marrow transplantation, cyclosporine and tacrolimus have proven theireffectiveness. However, their handling remains difficult because of a narrow therapeuticwindow and high inter- and intra-individual pharmacokinetic variabilities. Therapeutic drugmonitoring and dose adjustments of these drugs are necessary to reduce the risk of rejectionand minimize their toxicity.A PBPK model is built from anatomical, physiological and biochemical data. It can provideinformation on the kinetics in tissues and on the effects of physiological or pathologicalalterations.How to best administer cyclosporine in pediatric bone marrow transplantation, as well astherapeutic ranges to achieve, are discussed. A PBPK-PD model for cyclosporin built fromdata in the rat and then extrapolated and validated in humans was used to estimate exposure tocyclosporine in the target organs of GVHD, to compare schedules of administration byintravenous infusion, and to define target blood concentration based on therapeuticindications.Dose adjustment of tacrolimus in liver transplant patients by the Bayesian method is relativelyinaccurate in the initial period after transplantation because factors of variability areincompletly understood. A PBPK model was constructed and evaluated in order to findrelevant covariates by a bottom-up approach. Liver function, hematocrit, cytochrome P4503A5 genotype of the donor, the unbound fraction and some comedications were found. Newdosing regimen recommendations have been developed from this model
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Schuster, Carina [Verfasser], and Michael [Akademischer Betreuer] Vogeser. "Investigation and development of stable isotope dilution mass spectrometry methods for therapeutic drug monitoring of anti-infective drugs used in the critically ill / Carina Schuster ; Betreuer: Michael Vogeser." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1212362896/34.
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Giodini, Luciana. "Innovative Strategies for the Personalization of the Therapy in Cancer Patients. From Pharmacogenetics to Therapeutic Drug Monitoring: Different Approaches for Optimizing the Chemotherapy Dosing." Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424374.
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Most of the chemotherapeutic agents are characterized by a low therapeutic index and significant variability in therapeutic and toxic effects.
For this reason, many efforts have been made to optimize the dosage and the administration of antiblastic drugs in order to obtain a maximal anti-tumor effect with acceptable levels of toxicity.
The recent progresses in the cancer field introduced the concept of personalized therapy with the aim of tailoring medical treatment to the individual characteristics and needs of the single patient.
The personalization of the dosage could be obtained with different approaches depending on the molecular peculiarities of each drug and on the genetic characteristics of the patients.
In particular, in this thesis two different strategies were applied to optimize the chemotherapeutic treatment with fluoropirimidines, irinotecan, and sunitinib.
The first strategy concerns a pharmacogenetics approach with the purpose of optimizing the fluoropirimidines and the irinotecan dosage based on genetic biomarkers predictive of severe toxicities.
Regarding the fluoropyrimidines, the aim of the study was to introduce, in the clinical practice, a pre-treatment test for polymorphisms (SNPs) within the DPYD gene, able to predict the development of severe toxicities related to these drugs.
Furthermore, a genotype-driven phase Ib study was designed to optimize the irinotecan dosage: according to UGT1A1*28 genotype, the dosage of irinotecan was chosen for metastatic colorectal cancer (mCRC) patients treated with FOLFIRI (fluorouracil in association with irinotecan) plus cetuximab regimen.
In addition to this, another treatment tailoring strategy was applied, that is the therapeutic drug monitoring (TDM) of sunitinib. This approach aimed to monitor the plasmatic drug concentration in order to maintain it within the therapeutic window.
Aims
-Fluoropyrimidines project: a retrospective study was designed with the aim of validating the speci?city of three DPYD SNPs in predicting the occurrence of severe toxicity events in a large set of oncological patients. The secondary aim of this study was to evaluate whether the additional testing of other investigational DPYD variants could increase the pharmacogenetic test sensitivity.
-Irinotecan project: a phase 1b study was designed with three principal aims: 1) to define the Maximum Tolerated Dose (MTD), administered in the FOLFIRI regimen plus cetuximab in mCRC patients treated as first-line chemotherapy according to UGT1A1*28 genotype; 2) to evaluate the variability of irinotecan pharmacokinetics (PK), in combination with cetuximab, in patients with *1/*1 and *1/*28 genotype and the effect of the PK profile on toxicity and response rate; 3) to evaluate a possible effect of cetuximab on the PK of irinotecan.
-Sunitinib project: the project aimed to develop and validate, according to the FDA guidelines, an analytical method for the quantification of sunitinib and its main metabolite, N-desethyl sunitinib.
Methods
Each project of this thesis considered the application of different methodologies depending on the characteristic of the study.
The methods for SNPs genotyping performed for the pharmacogenetic analysis were set up and developed using three different methodologies: Pyrosequencing, TaqMan® Allelic Discrimination Assay, and automated direct sequencing.
Regarding the PK analyses and the TDM approach, two HPLC-MS/MS methods were applied.
Results
-Fluoropyrimidines project: data from this study demonstrated the clinical validity and specificity of the three DPYD SNPs genotyping test to prevent FL-related Grade =3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice.
-Irinotecan project: at the moment, one patient was enrolled in this study. The PK of the enrolled patient was followed during the days 1-3 and the days 15-17. The main PK parameters of CPT-11 and its metabolites of the first patient enrolled were calculated trough a non-compartmental analysis.
-Sunitinib project: the method was setup and validated for the quantification of sunitinib and its main metabolite with a diagnostic perspective. The obtained method resulted easy, rapid and feasible for the clinical routine.
Conclusions
The different approaches described in this PhD thesis shared the same final aim: to translate the research results in the clinical practice and, consequently, to ameliorate cancer patients’ life. In this perspective, the results of this thesis strongly encourage the introduction of the personalized therapy in the cancer field, where the optimization of the chemotherapy dosing is a compelling need<br>La maggior parte degli agenti chemioterapici è caratterizzata da un basso indice terapeutico e da una elevata variabilità interpaziente sia nella risposta alla terapia che nello sviluppo di tossicità.
Per questo motivo, la comunità scientifica ha investito molto nell’ottimizzazione del dosaggio dei chemioterapici con il fine ultimo di ottenerne la massima efficacia con accettabili livelli di tossicità. A tal proposito, i recenti progressi nel campo della medicina oncologica hanno portato all’introduzione del concetto di terapia personalizzata. Tale approccio propone di individuare il giusto trattamento per ogni singolo individuo, basandosi sulle sue caratteristiche e necessità.
La personalizzazione della terapia chemioterapica può essere ottenuta tramite diversi approcci che dipendono sia dalle proprietà e caratteristiche molecolari del farmaco sia dalle peculiarità del singolo paziente. Questo lavoro di tesi si inserisce in questo filone di ricerca. In particolar modo, sono stati perseguiti due diversi approcci al fine di ottimizzare il trattamento con fluoropirimidine, irinotecano e sunitinib.
Il primo approccio selezionato si basa sull’applicazione delle conoscenze ottenute dalla farmacogenetica, disciplina che ha lo scopo di identificare il ruolo di varianti genetiche, polimorfismi (SNP), nella risposta al trattamento in termini sia di efficacia che di rischio di sviluppo di tossicità. In tale fase, la potenzialità dell’utilizzo di SNP predittivi di tossicità grave è stata studiata per migliorare il dosaggio di fluoropirimidine ed irinotecano.
Nel caso delle fluoropirimidine è stato disegnato uno studio retrospettico con lo scopo di definire la validità clinica di un test genetico pre-trattamento per alcuni SNP nel gene della DPYD al fine di valutare la capacità di questo test di predire lo sviluppo di tossicità gravi correlate a tale tipo di trattamento. Lo scopo di questo studio è di introdurre nella pratica clinica tale test al fine di migliorare la qualità di vita dei pazienti cui vengono somministrati questi farmaci.
Un’ altra applicazione delle conoscenze della farmacogenetica analizzata in questa tesi è rappresentata dagli studi di fase Ib basati sul genotipo, strategia che è stata perseguita per ottimizzare il dosaggio dell’irinotecano. Più in dettaglio, la massima dose tollerata (MTD) di tale farmaco è stata valutata in base al polimorfismo UGT1A1*28 in pazienti con cancro metastatico al colon retto trattati con il regime FOLFIRI (5-fluorouracile associato con irinotecano) e cetuximab.
Infine, un’altra strategia che riguarda la personalizzazione della terapia è rappresentata dal monitoraggio terapeutico del farmaco (TDM). Questo approccio è stato applicato per il sunitinib in modo da monitorarne le concentrazioni plasmatiche e mantenerle all’interno di una finestra terapeutica.
Scopo
-Fluoropirimidine: è stato disegnato uno studio retrospettico con il fine ultimo di validare la specificità di tre SNP della DPYD nel predire l’insorgenza di tossicità grave in un’ampia casistica di pazienti oncologici. Scopo secondario di questo studio è stata quello di valutare se l’analisi di altre varianti del gene della DPYD possano migliorare la sensibilità del test farmacogenetico.
-Irinotecano: è stato disegnato uno studio di fase 1b con i seguenti scopi: 1) definire la MTD, in base al genotipo UGT1A1*28, in pazienti metastatici con tumore al colon retto trattati con regime FOLFIRI associato a cetuximab; 2) valutare la variabilità dei parametri farmacocinetici dell’irinotecano, in combinazione con cetuximab, in pazienti con genotipo UGT1A1*1/*1 e UGT1A1*1/*28 e analizzare il possibile effetto del profilo farmacocinetico sulla tossicità e risposta; 3) stabilire se il cetuximab ha un effetto sulla farmacocinetica dell’irinotecano.
-Sunitinib: lo scopo di questo progetto è lo sviluppo e la validazione, in base alle linee guida rilasciate dalla Food and Drug Administration (FDA), di un metodo bioanalitico per quantificare sia il sunitinib sia il suo metabolita attivo, N-desetil sunitinib.
Materiali e metodi
In base agli scopi e alle peculiarità dei singoli progetti di questa tesi sono state applicate specifiche metodiche.
I metodi messi a punto ed utilizzati per le analisi farmacogenetiche sono i seguenti: pyrosequencing, saggio Taqman per la discriminazione allelica e sequenziamento diretto automatizzato.
Per quanto riguarda invece le analisi di farmacocinetica sono stati utilizzati due metodi in HPLC-MS/MS, uno dei quali, il metodo del sunitinib, è stato messo a punto e validato secondo le linee guida FDA.
Risultati
-Fluoropirimidine: i dati ottenuti da questo studio hanno dimostrato la validità clinica e la specificità del test farmaco genetico pre-trattamento basato sulla DPYD per prevenire l’insorgenza di tossicità gravi di grado =3. Tali risultati incoraggiano l’introduzione di questo test nella pratica clinica.
-Irinotecano: al momento una sola paziente è stata ritenuta eleggibile secondo i criteri dello studio. La farmacocinetica di CPT-11 e dei suoi principali metaboliti è stata descritta grazie a prelievi ripetuti durante la prima (giorni 1-3) e la seconda (giorni 15-17) somministrazione. Sono stati inoltre calcolati i principali parametri farmacocinetici di CPT-11 e dei suoi metaboliti tramite l’applicazione di un’analisi non compartimentale.
-Sunitinib: il metodo per la quantificazione del sunitinib e del suo metabolita attivo è stato messo a punto e validato. Considerata la facilità e la rapidità di tale analisi , si può auspicare che tale metodo possa essere facilmente applicabile nella pratica clinica.
Conclusioni
Gli approcci descritti in questa tesi condividono lo stesso scopo finale: traslare, cioè, i risultati della ricerca nella pratica clinica e, di conseguenza, migliorare la vita dei pazienti oncologici. In questa ottica, i risultati di questo lavoro incoraggiano fortemente l’introduzione di una terapia personalizzata nel campo oncologico, dove urge la necessità di nuovi approcci per ottimizzare il dosaggio dei farmaci
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Stallard, Derek, and Stacy D. Brown. "Comparing HPLC Stationary Phases for The Separation of Six Compounds Used in Pain Management: Is There a Viable Alternative to C18?" Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/5297.
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In this study, four different chromatographic column chemistries (octadecylsilane/ C18, pentafluorophenyl/ PFP, octadecylated polystyrene-divinylbenzene/ PRP and underivatized silica/ HILIC) were compared under optimal conditions to evaluate the relative strengths and weaknesses of the phases for use in the determination of pain management drugs by LC-MS. Furthermore, different column scaffoldings, traditional silica, porous shell, and porous polymer, were also compared. The drugs included in this study included buprenorphine, fentanyl, methadone, naloxone, oxycodone, and tramadol. Factors such as peak area, peak resolution, theoretical plates, and reproducibility were compared among the columns and analytes using a 2-way analysis of variance (ANOVA). Because of the lipophilic nature of these drugs, the C18 columns tended to offer the best performance; however, PFP and PRP columns were viable alternatives. Finally, HILIC separation was also suitable for most of the compounds under study; often providing higher peak areas (sensitivity) likely associated with higher organic (% B) conditions, thus favoring mass spectrometric detection. To our knowledge, this is the first study to explore viability of other non-C18 stationary phases such as PRP and HILIC for this drug class.
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Bossaer, John B., and Paul O. Lewis. "Antibiotic Use in Home Health: A Primer." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etsu-works/2316.
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Cost containment measures within hospital systems push for earlier discharges on stable patients. Due to patient placement difficulties and costs associated with skilled facilities, antibiotic use in home health care settings is becoming a common occurrence. This trend will likely increase as care continues to shift to outpatient areas. Lack of sufficient serum drug concentrations needed in severe infections and increasing resistance to many of the oral options often necessitates the use of the intravenous (IV) route. Home health care practitioners may have minimal information on patients or limited experience with IV antibiotics that may impact quality of care. This review summarizes key points relevant to IV antibiotics routinely used by home health prescribers, nurses, technicians, and care managers. This review will focus on antibacterial agents including vancomycin, aminoglycosides, beta-lactams, daptomycin, tigecycline, and telavancin. Appropriate dosing, indications, adverse events, monitoring parameters, and feasibility of using IV antibiotics are discussed.
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Muneer, Saiqa. "Novel nanoformulations and nanosensors for bioactive molecules of biomedical significance." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/213224/1/Saiqa_Muneer_Thesis.pdf.
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This thesis demonstrates novel nanosensors and nanomaterials for the sensitive detection of bioactive molecules (antibody therapeutics and antibiotics) in complex biological matrices utilizing thiol chemistry for label-free SERS detection. In addition to biomedical analysis, formulation development of dry powder inhalers overcomes the issues of adverse effects associated with parenteral or oral route of drug administration. It is expected to accomplish the key requisites like aerosolization properties, physicochemical characteristics, biocompatibility, and biodegradation with minimal side effects. Therefore, this study provided a motivation to address current advancement of detection techniques and development of novel drug delivery systems for the bioactive molecules.
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Rousset, Marine. "Etude des déterminants de l’efficacité et la toxicité des inhibiteurs de kinase utilisés dans le traitement du mélanome métastatique." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0266.
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Le traitement par BRAF-inhibiteur (BRAFi) et MEK-inhibiteur (MEKi) en association a permis d’améliorer significativement la survie des patients atteints de mélanome métastatique muté BRAFV600. Cette mutation est présente chez 50 % des patients. Les BRAFi et MEKi sont des inhibiteurs de protéines kinase, dont le métabolisme fait intervenir le CYP 3A4, à l’origine de grandes variabilités des concentrations plasmatiques inter-patients pour une même dose administrée. La moitié des patients répondent au traitement, et 90% des patients présentent des effets indésirables, nécessitant une diminution de la posologie dans 33% des cas. Dans ce contexte, nous avons décrit les effets indésirables de chacun des BRAFi et MEKi et, pour ceux qui sont dose-dépendants, nous avons cherché à établir un lien entre concentration plasmatique et survenue d’effet indésirable. Grace à la mise au point d’une méthode analytique en chromatographie liquide couplée à la spectrométrie de masse, nous avons mesuré prospectivement les concentrations plasmatiques des BRAFi et MEKi chez les patients bordelais. Ces données permis de définir un seuil de toxicité de 48 ng/ml pour le dabrafenib. La définition de ce seuil constitue une étape essentielle à la conduite d’une étude randomisée visant à évaluer l’intérêt du suivi thérapeutique pharmacologique<br>The combination of BRAF-inhibitors (BRAFi) and MEK-inhibitors (MEKi) has significantly improved the survival of patients with metastatic melanoma with BRAFV600 mutation. About 50% of patients harbour BRAFV600 mutation. BRAFi and MEKi are kinase inhibitors, metabolized by CYP 3A4, responsible for large between-patients variability in plasma concentrations for the same administered dose. About half of patients respond to treatment, and 90% of patients present adverse drug reactions (ADR), requiring dose reduction in 33% of cases. In this context, we described ADR profiles of each of the BRAFi and MEKi in the global pharmacovigilance database, and for ADR that are dose-dependent; we looked for the link between plasma exposure to the drug and the occurrence of ADR. Using the assay method developed, we prospectively measured the plasma concentrations of BRAFi and MEKi in Bordeaux patients, which allowed us to define a toxicity threshold of 48 ng / ml for dabrafenib. This work allowed to deepen the knowledge on the profiles and the occurrence of the ADR for each BRAFi and MEKi. The definition of a toxicity threshold for dabrafenib is a prerequisite for a randomized study to evaluate the value of therapeutic drug monitoring
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Moeung, Sotheara. "Evaluation du suivi thérapeutique pharmacologique du carboplatine et étude pharmacocinétique-pharmacogénétique de l'étoposide dans le cadre d'un essai clinique de phase II d'intensification thérapeutique en cancérologie." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30146/document.
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Le protocole TICE (Taxol, Ifosfamide, Carboplatine et Etoposide) représente le traitement standard du cancer germinal réfractaire en première ligne ou en rechute de mauvais pronostic. Une étude de phase II a été réalisée consistant en une adaptation de posologie du carboplatine (utilisé à haute dose) basée sur un suivi thérapeutique pharmacologique (TDM) de ses concentrations ultrafiltrables (UF) alors que les pratiques habituelles se limitent à des doses calculées à partir d'une valeur cible de l'aire sous la courbe (AUC) des concentrations UF et la clairance UF prédite du patient. Les analyses pharmacocinétiques effectuées dans le cadre de cette thèse ont permis de démontrer la faisabilité du TDM ainsi que sa performance dans la maîtrise de l'AUC du carboplatine utilisé dans le protocole TICE. Cependant, la réalisation de cette pratique est limitée, dans certains hôpitaux, par les contraintes matérielles et humaines liées à l'obtention des concentrations UF par l'ultrafiltration des prélèvements plasmatiques. Une méthodologie a donc été développée et validée pour permettre la réalisation du TDM à partir des concentrations plasmatiques totales. Par ailleurs, l'étude pharmacocinétique réalisée pour l'étoposide, médicament associé au carboplatine dans la phase d'intensification de ce protocole, indique que le calcul actuel de la dose en fonction de la surface corporelle s'accompagne d'une variabilité interindividuelle limitée de l'exposition et qu'il n'y a pas lieu de pratiquer un TDM pour ce médicament. Enfin, l'implication de différents facteurs génétiques correspondant, d'une part, à la toxicité auditive du carboplatine et, d'autre part, à la pharmacologie de l'étoposide a été aussi évaluée. En conclusion, ces travaux permettront d'améliorer la prise en charge des patients traités par ce protocole à haute dose de carboplatine et étoposide et, au-delà de cette indication thérapeutique, notre connaissance de ces deux médicaments cytotoxiques importants<br>The TI-CE protocol ((Taxol, Ifosfamide, Carboplatin and Etoposide) is the standard treatment of germ cell tumor refractory to first-line chemotherapy or relapsed germ cell tumor having unfavorable prognostic features. A phase II study was conducted and consisted in adapting the dose of (high dose) carboplatin using therapeutic drug monitoring (TDM) of unbound concentrations instead of the usual method of dose individualization based on a target area under the curve (AUC) of unbound concentrations and predicted unbound clearance. Pharmacokinetic analyses carried out in the context of this thesis have demonstrated the feasibility of conducting the TDM as well as its performance in terms of controlling the variability of AUC of carboplatin in the TI-CE protocol. However, the use of this practice is limited, in some hospitals, by material and human constraints related to the ultrafiltration of plasma samples to obtain unbound concentrations. A method was developed and validated to enable the use of total plasma concentrations for the TDM instead of unbound concentrations. Furthermore, the pharmacokinetic study of etoposide, used in combination with carboplatin during the dose intensification phase of the protocol, showed that the usual dose calculation method based on body surface area is associated with a low interindividual variability of exposure and that TDM is, therefore, not necessary for this drug. Finally, the role of different genetic factors in the ototoxicity of carboplatin and in the pharmacology of etoposide was also assessed. In conclusion, these analyses help to improve the level of care of patients treated with this protocol of high dose carboplatin and etoposide as well as our current knowledge of these two important cytotoxic drugs
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Onuoha, Mary Remigius Agatha Verfasser], and Ekkehard [Akademischer Betreuer] [Haen. "Therapeutic Drug Monitoring of Antipsychotics - HPLC Analytical Method Development and Pharmaceutical Advices to the Ward Clinicians - For Successful Individualized Therapy / Mary Remigius Agatha Onuoha ; Betreuer: Ekkehard Haen." Regensburg : Universitätsbibliothek Regensburg, 2016. http://d-nb.info/1121302726/34.
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Onuoha, Mary Remigius Agatha [Verfasser], and Ekkehard [Akademischer Betreuer] Haen. "Therapeutic Drug Monitoring of Antipsychotics - HPLC Analytical Method Development and Pharmaceutical Advices to the Ward Clinicians - For Successful Individualized Therapy / Mary Remigius Agatha Onuoha ; Betreuer: Ekkehard Haen." Regensburg : Universitätsbibliothek Regensburg, 2016. http://d-nb.info/1121302726/34.
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Horn, Je'nine. "The analysis of 6- and 24-hour iodine-131 thyroid uptake in patients with Graves' disease at Universitas Hospital." Thesis, [Bloemfontein?] : Central University of Technology, Free State, 2007. http://hdl.handle.net/11462/102.
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Thesis (M.Tech.)(Nuclear Medicine) -- Central University of Technology, free State, 2007<br>In the South African Health Services (SAHS) it is each health worker’s responsibility to find ways to reduce health care cost and improve health service to the public. The measurement of radioactive iodine uptake (RAIU) by the thyroid gland for diagnostic purposes has been used as early as the 1940s. The 24-hour (hr) iodine-131 (131I) uptake measurement is traditionally used for the calculation of the 131I administered activity for therapy dosage. This entails that the patient’s hospitalisation is prolonged, which increases the costs. The literature also indicates that the 24-hr 131I uptake value can be discarded and only the 6-hr 131I uptake measurement is needed to calculate administered activity for therapeutic dosages for Graves’ patients. Therefore, if it can be confirmed that the 6-hr 131I uptake measurement alone is needed, the SAHS could decrease hospitalisation costs. The overall goal of the investigation was to analyse the 6-hr and 24-hr 131I uptake measurements of patients with Graves’ disease at the Universitas Hospital. The aim was to determine the relationship between the 6-hr and 24- hr RAIU values to establish the therapeutic dosage for Graves’ disease.
To achieve the aim, three objectives were set. First, to serve as a background to the investigation, a literature survey relating to the RAIU measurements of patients with Graves’ disease was made. Second, a retrospective analysis was performed by collecting the 6-hr and 24-hr 131I uptake measurements of patients with proven Graves’ disease at the Universitas Nuclear Medicine Department (UNMD). Finally, the data obtained from the retrospective analysis was analysed, summarised and compared to answer the investigation questions.
The investigation group included patients with confirmed Graves’ disease who had undergone both the 6- and 24-hr 131I RAIU at the Universitas Hospital from the beginning of 2004 to the end of 2005. Graves’ disease is confirmed by the following factors at the UNMD, namely: Suppressed TSH, elevated T4 and T3 values, an increased uptake on the 99mTc-pertechnetate scan and increased 6- and 24-hr 131I RAIU values. The UNMD statistics show that 178 patients were diagnosed with Graves’ disease during this period. The patients of the investigation group included both male and female patients from different races, ranging from 15-75 years. In order to increase the validity of the investigation, all factors that could influence the accuracy of the 131I thyroid uptake test were excluded. After the exclusion and inclusion criteria had been applied, the final investigation group was made up of 124 Graves’ disease patients.
The data obtained from the patient files was noted on the different data sheets (see Appendix A) for further analysis. The information from these data sheets was then used to obtain the investigation results. The Department of Biostatistics of the University of the Free State (UFS) was consulted for recommendations regarding the management of data and the processing of results. All values were summarised by means and Standard Deviations (SD) or percentiles. Mean or median differences were calculated with a 95% Confidence Interval (CI). A regression analysis was made between the 6-hr and 24-hr 131I RAIU values.
The highest RAIU value is the best to calculate the therapeutic dosage, as this gives a true reflection of the thyroid function of a Graves’ disease patient. In the investigation group the median of the 24-hr 131I RAIU values was higher than the 6-hr 131I RAIU values. The findings showed that the 24-hr 131I RAIU in most of the investigation group was the highest value and most effective to calculate the 131I therapeutic dosage.
At a time when research-based practice is taking on an increasingly important role, it is essential for nuclear medicine departments to make evidence-based recommendations. This investigation found that the correlation between the 6-hr and 24-hr RAIU clearly justified the cost spent on Graves’ disease patients who must stay overnight for the 24-hr 131I RAIU procedure.
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Valle, T. Figueras José María. "Variabilitat, efectivitat i seguretat del voriconazole en la infecció fúngica invasiva a pediatria." Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670947.
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Introducció. Les concentracions plasmàtiques (CP) de voriconazole (VCZ) tenen una elevada variabilitat. El 2012 va canviar la posologia del VCZ a pediatria. Existeixen poques dades pediàtriques sobre el monitoratge de CP (MCP) de VCZ amb la dosificació actual. Es pretén avaluar el MCP i descriure la seva relació amb l’efectivitat i seguretat del tractament de la infecció fúngica invasiva (IFI) a pediatria amb la nova posologia.
Mètodes. Estudi prospectiu observacional unicèntric, realitzat des de gener de 2014 fins agost de 2018 amb pacients de 2-12 anys en tractament amb VCZ a les dosis actuals, amb MCP setmanal i una pauta de canvi de dosi en funció del valor de les CP. Es categoritza la IFI com a provada/probable/possible segons els criteris diagnòstics del grup EORTC/MSG i s’avalua la resposta al tractament segons els criteris del mateix grup. Els efectes adversos (EA) es classifiquen mitjançant la taula americana Common Terminology Criteria for Adverse Events. Es registren també altres factors que poden afectar les CP.
Resultats. S’han obtingut 229 CP de 28 episodis d’IFI (18 IFI provada/probable). La durada del tractament entre els episodis d’IFI provada/probable ha estat de 83,5 dies (5-896). El 64,2% de les CP van ser terapèutiques (1-5,5 mg/L), el 27,5% infraterapèutiques i el 8,3% supraterapèutiques. La pauta de modificació de dosi quan les CP estaven fora del rang terapèutic ha aconseguit corregir el 75% dels valors quan s’ha seguit correctament el protocol. La primera setmana de tractament hi ha hagut més CP infraterapèutiques (43,5%) que la resta del període (25,9%) (p=0,07). La dosi mitjana per a aconseguir unes CP terapèutiques en pacients de 2-7 anys (21 mg/kg/dia) ha estat més alta que en pacients més grans (p=0,02) i que la recomanada actualment. En pacients de 2-7 anys s’ha objectivat una relació lineal entre la dosi i el valor de les CP (p=0,01). La hipoalbuminèmia greu (p=0,02) i l’elevació de la proteïna C reactiva (CRP) (p=0,03) s’han associat a un pitjor control de les CP. L’efectivitat del tractament ha estat del 60% en l’avaluació precoç i del 53,3% en l’avaluació tardana. La supervivència als 6 mesos ha estat del 80%, sense èxitus atribuïts a la IFI. Les alteracions hepàtiques han estat l’EA més freqüent (88,9% dels pacients), majoritàriament de baix grau. Els EA visuals, neurològics, gastrointestinals, cutanis o renals s’han produït en menor freqüència (<10%). L’adequació de les CP s’ha associat amb major efectivitat del tractament en l’avaluació tardana (p=0,03). Les CP >5,5 mg/L s’han relacionat amb alteracions hepàtiques (p=0,02) i renals (p=0,03).
Conclusions. La variabilitat de les CP de VCZ amb la nova posologia és encara elevada i es veu influïda pel valor de l’albúmina i de la CRP, relacionades amb la inflamació sistèmica. La dosi necessària per a aconseguir unes CP correctes en pacients de 2-7 anys és superior a la recomanada. La pauta de modificació de dosi proposada al nostre treball sembla ser efectiva. El tractament amb la nova posologia és efectiu i segur, però les alteracions dels enzims hepàtics són freqüents. Les CP de VCZ es relacionen amb l’efectivitat i la seguretat del tractament amb la nova posologia. Cal continuar realitzant el MCP de VCZ i plantejar-se la necessitat d’augmentar la dosi de VCZ en els pacients més petits, de protocol·litzar el canvi de dosi en funció del valor de les CP i de realitzar un control estricte de la inflamació sistèmica.<br>Introducción. Las concentraciones plasmáticas (CP) de voriconazole (VCZ) tienen una elevada variabilidad. El 2012 cambió la posología del VCZ en pediatría. Existen pocos datos pediátricos sobre la monitorización de CP (MCP) de VCZ con la dosificación actual. Se pretende evaluar la MCP y describir su relación con la efectividad y seguridad del tratamiento de la infección fúngica invasiva (IFI) en pediatría con la nueva posología.
Métodos. Estudio prospectivo observacional, realizado en un solo centro desde enero de 2014 hasta agosto de 2018 con pacientes de 2-12 años en tratamiento con VCZ a las dosis actuales, con MCP semanal y una pauta de cambio de dosis en función del valor de las CP. Se categoriza la IFI como probada/probable/posible según los criterios diagnósticos del grupo EORTC/MSG y se evalúa la respuesta al tratamiento según los criterios del mismo grupo. Los efectos adversos (EA) se clasifican mediante la tabla americana Common Terminology Criteria for Adverse Events. Se registran también otros factores que pueden afectar las CP.
Resultados. Se han obtenido 229 CP de 28 episodios de IFI (18 IFI probada/probable). La duración del tratamiento entre los episodios de IFI probada/probable ha sido de 83,5 días (5-896). El 64,2% de las CP fueron terapéuticas (1-5,5 mg/L), el 27,5% infraterapéuticas y el 8,3% supraterapéuticas. La pauta de modificación de dosis cuando las CP estaban fuera del rango terapéutico ha logrado corregir el 75% de los valores cuando se ha seguido correctamente el protocolo. La primera semana de tratamiento ha habido más CP infraterapéuticas (43,5%) que el resto del periodo (25,9%) (p=0,07). La dosis media para conseguir unas CP terapéuticas en pacientes de 2-7 años (21 mg/kg/día) ha sido más alta que en pacientes más mayores (p=0,02) y que la recomendada actualmente. En pacientes de 2-7 años se ha objetivado una relación lineal entre la dosis y el valor de las CP (p=0,01). La hipoalbuminemia grave (p=0,02) y la elevación de la proteína C reactiva (CRP) (p=0,03) se han asociado a un peor control de las CP. La efectividad del tratamiento fue del 60% en la evaluación precoz y del 53,3% en la evaluación tardía. La supervivencia a los 6 meses fue del 80%, sin fallecimientos atribuidos a la IFI. Las alteraciones hepáticas han sido el EA más frecuente (88,9% de los pacientes), en su mayoría de escasa gravedad. Los EA visuales, neurológicos, gastrointestinales, cutáneos o renales se han producido con menor frecuencia (<10%). La adecuación de las CP se ha asociado a mayor efectividad del tratamiento en la evaluación tardía (p=0,03). Las CP >5,5 mg/L se han relacionado con alteraciones hepáticas (p=0,02) y renales (p=0,03).
Conclusiones. La variabilidad de las CP de VCZ con la nueva posología es todavía elevada y se ve influida por el valor de la albúmina y de la CRP, relacionadas con la inflamación sistémica. La dosis necesaria para conseguir unas CP correctas en pacientes de 2-7 años es superior a la recomendada. La pauta de modificación de dosis propuesta en nuestro estudio parece ser efectiva. El tratamiento con la nueva posología es efectivo y seguro, pero las alteraciones en las enzimas hepáticas son frecuentes. Las CP de VCZ se relacionan con la efectividad y la seguridad del tratamiento con la nueva posología. Hay que seguir realizando el MCP de VCZ y plantearse la necesidad de aumentar la dosis de VCZ en los pacientes más pequeños, de protocolizar el cambio de dosis en función del valor de las CP y de realizar un control más estricto de la inflamación sistémica.<br>Background. It is known that voriconazole (VCZ) plasma levels (PL) are highly variable. Dose recommendation changed in 2012 for paediatric patients between 2 and 12 years old (yo). Little data on therapeutic drug monitoring (TDM) after these new recommendations is available. We aim to evaluate TDM of VCZ in paediatric patients with invasive fungal infection (IFI) and its relationship with safety and effectiveness.
Methods. Prospective observational single-centre study from January 2014 to August 2018. All consecutive patients aged 2-12 yo receiving VCZ were included. TDM was performed weekly and doses were changed according to local protocol. IFI were categorized as possible/probable/proven according to EORTC/MSG group criteria, response to treatment was evaluated according to same group criteria and adverse events were recorded following the Common Terminology Criteria for Adverse Events. Factors potentially influencing PL were analysed.
Results. We obtained 229 PL from 28 IFI episodes (18 probable/proven). Duration of treatment in proven/probable episodes was 83.5 days (5-896). 64.2% of PL were therapeutic (1-5.5 mg/L), but more than one-third of them weren’t: 27.5% below; 8.3% above. After dose modification according with our protocol, 75% therapeutic PL were achieved. In the first week of treatment there were more infratherapeutic PL (43.5%) than the rest of the period (25.9%) (p=0.07). Dose to achieve therapeutic PL in patients below 8 yo (21mg/kg/day) was higher than recommended and higher than in older patients. In these patients, a linear relationship between dose and PL value was observed (p=0.01). Severe hypoalbuminemia (p=0,02) and marked elevation of C-reactive protein (CRP) (p=0,03) were associated with worse PL adequacy. The effectiveness of treatment was 60% in the early evaluation and 53.3% in the late evaluation. Survival at 6 months was 80%, with no deaths attributed to IFI. Non-infratherapeutic PL were associated with better treatment response at late evaluation, and supratherapeutic PL were associated with liver (p=0,02) and renal dysfunction (p=0,03).
Conclusions. VCZ PL variability remains high despite current updated recommendations and it’s influenced by severe hypoalbuminemia and increased CRP. Therefore, additional efforts to control inflammation in children with IFI should be encouraged. Our dose modification recommendation appears to be effective. Treatment with the new dosage is effective and safe, but alterations in liver enzymes are common. Therapeutic VCZ PL are related to treatment effectiveness and safety; thus, TDM of VCZ is mandatory. Higher doses should be considered in patients below 8 yo. It’s necessary to consider protocolizing the dose modification based on the value of the PL.
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Åkerblad, Ann-Charlotte. "Adherence to Antidepressant Medication." Doctoral thesis, Uppsala University, Department of Neuroscience, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7769.
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<p>Non-adherence to medication is a major obstacle in the treatment of depression. The objectives of the present study were to explore the effect of two interventions aiming to increase antidepressant treatment adherence, and to examine long-term consequences and costs of depression in adherent and non-adherent primary care patients. </p><p>A randomised controlled design was used to assess the respective effects of a written educational adherence enhancing programme and therapeutic drug monitoring in patients with major depression treated with sertraline for 24 weeks. All patients were prospectively followed during two years. </p><p>Treatment adherence was found in 41% of the 1031 included patients. None of the interventions resulted in a significant increase in adherence rate. However, significantly more patients in the group receiving the written educational material had responded at week 24 as compared to patients in the control group. </p><p>The overall remission rate after two years was 68%. In total, 34% of the responders experienced at least one relapse. Response and remission rates at week 24, year 1 and year 2 were significantly higher in adherent as compared to non-adherent patients. No relationship between adherence and relapse rate was seen. </p><p>The mean total cost per patient during two years was KSEK 363 whereof indirect costs represented 87%. No significant differences in costs between intervention groups or between adherent and non-adherent patients could be demonstrated. However, the mean cost per patient was 39% lower for treatment responders as compared to non-responders. </p><p>Non-adherence was predicted by age below 35 or above 64 years, no concomitant medications, personality disorder, sensation seeking personality traits and substance abuse. </p><p>The results indicate a strong positive relationship between treatment adherence and clinical outcome. In addition, the study shows that depression is a costly disease and that certain patient characteristics predict non-adherence.</p>
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Silva, Bruno José Gonçalves da. "Avaliação técnica SPME/LC na análise de antidepressivos em amostra de plasma para fins de monitorização terapêutica." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/59/59138/tde-17082007-114009/.
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As recentes técnicas miniaturizadas de preparo de amostra, microextração em fase sólida (SPME) e in tube SPME, apresentam uma série de vantagens em relação aos métodos clássicos de extração (extração líquido-líquido e extração em fase sólida), tais como: não requer instrumentação analítica sofisticada, utilização de pequenas quantidades de solventes orgânicos, rápido processo operacional, permite automação das análises, a reutilização das fases extratoras, e integra em um único sistema a extração, concentração e introdução da amostra no cromatográfico. Esta dissertação tem como objetivo a padronização, validação e comparação dos métodos SPME/LC-UV com dessorção off line e in tube SPME/LC-UV, para a análise dos antidepressivos da nova geração (mirtazapina, citalopram, paroxetina, duloxetina, fluoxetina e sertralina) em amostras de plasma para fins de monitorização terapêutica. As variáveis: fase extratora, pH da matriz, tempo e temperatura de extração e de dessorção e força iônica apresentaram grande influência na eficiência do processo SPME. O método SPME/LC-UV padronizado, apresentou limite de quantificação (LQ) de 25 a 50 ng mL-1, ampla faixa de linearidade (LQ ? 500 ng mL-1, r2 > 0,9970) e precisão inter ensaios com coeficientes de variação menor que 15% para todos os analitos. Apesar das baixas taxas de recuperação obtidas, de 8,1% (citalopram) a 17,1% (mirtazapina), o método SPME/LC-UV apresentou seletividade e sensibilidade analítica adequada. As variáveis: pH da matriz, fluxo e número de ciclos aspirar/dispensar e volume de amostra apresentaram grande influência na eficiência do processo in tube SPME. A etapa de precipitação de proteínas do plasma, anterior ao processo de extração, foi necessária para a eliminação dos compostos endógenos. O método in tube SPME/LC-UV padronizado apresentou seletividade adequada, precisão inter ensaios com coeficiente de variação menor que 10%, LQ de 20 a 50 ng mL-1, linearidade na faixa de concentração do LQ a 500 ng mL-1, com r2 > 0,9983 para todos os analitos e recuperação absoluta de 5,32% (mirtazapina) a 43,5% (sertralina). A técnica in tube SPME, quando comparada à SPME, permitiu a automação das análises, menor exposição do analista às amostras biológicas e solventes orgânicos, menor tempo de análise e menor volume de amostra de plasma. A eficácia dos métodos, SPME/LC-UV e in tube SPME/LC-UV, foi comprovada através das análises de amostras de plasma de pacientes em terapia com os antidepressivos, para fins de monitorização terapêutica.<br>The recent miniaturized sample techniques preparation, solid phase microextraction (SPME) and in tube SPME, present several advantages when compared with classic extraction methods (liquid-liquid extraction and solid phase extraction), such as: it does not require sophisticated analytical instrumentation, use small organic solvent amounts, fast operational process, automation of the analyses, reuse extraction phases, and incorporates, into a single procedure, sample extraction, concentration and sample introduction. The aim of this work is development, validation and comparison of methods SPME/LC-UV with off line desorption and in tube SPME/LC-UV, for analyses of antidepressants of the new generation (mirtazapine, citalopram, paroxetine, duloxetine, fluoxetine and sertraline) in plasma samples for therapeutic drug monitoring. Variables: extraction phase, matrix pH, time and temperature of extraction and desorption and ionic strength showed great influence in SPME process efficiency. The method SPME/LC-UV presented limit of quantification (LOQ) variety from 25 to 50 ng mL-1, wide range the of linearity (LOQ 500 ng mL-1, r2 > 0.9970) and interassays precision with coefficient of variation lower than 15% for all analytes. Although the low recovery, from 8.1% (citalopram) to 17.1% (mirtazapine), the method SPME/LC-UV presented adequate selectivity and analytical sensitivity. Variables: matrix pH, flow and number of aspirate/dispense cycles and sample volume showed great influence in the in tube SPME process efficiency. The protein precipitation of the plasma steps, previous to the extraction process, was necessary for the endogenous compounds elimination. The method in tube SPME/LC showed adequate selectivity, interassays precision with coefficient of variation lower than 10%, LOQ variety from 20 to 50 ng mL-1, linearity in range concentration from LOQ to 500 ng mL-1, with r2 > 0.9983 for all analytes and recovery from 5.32% (mirtazapine) to 43.5% (sertraline). The technique in tube SPME, compared with the SPME, permitted the automation of the analyses, minor exposition of the analyst to the biological samples and organic solvent, shorter analyses time and minor plasma sample volume. The effectiveness methods, SPME/LC-UV and in tube SPME/LC-UV, was proven through the analyses of plasma samples of patients in therapy with antidepressants, for therapeutic drug monitoring.
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Lindman, Elin. "A spectrophotometric method to analyze antibiotics in plasma: A validation study." Thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-355556.
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Antibiotic resistance is one of the most serious medical problems in the world. To counteract the increase in antibiotic resistance, new rapid and effective analytical methods are needed. To effectively treat infections in critically ill patients, optimal antibiotic dosages are required. DrugLog® is an instrument that uses a spectrophotometric method to analyze antibiotics in plasma in the wavelength range 200-800 nm. The aim of this study was to do a method validation of the instrument DrugLog®. The study material that was used was whole blood from healthy donor and routine citrate plasma samples from the laboratory. The precision of the method and stability of plasma, the best way to filtrate lipids from plasma and four antibiotics (meropenem, cefotaxime, vancomycin, piperacillin/tazobactam) were investigated. The precision of the method, measured as CV% was less than 0.62 and stability plasma showed a CV% of 135.74 after 24 h in room temperature. The stability for the different antibiotics after 24 h in room temperature showed a CV% of 8.11 for meropenem, 40.80 for vancomycin, 16.55 for cefotaxime and 2.92 for the combination antibiotic piperacillin/tazobactam. It was also determined that bacterial filter was the best way to remove lipids from plasma. In conclusion DrugLog® is a suitable instrument to analyze concentration of antibiotics in patients during antibiotic treatment, however further validations are needed.
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Barau, Caroline. "Etude des facteurs influençant la pharmacocinétique de deux médicaments glucuronoconjugués, l'acide mycophénolique et le raltégravir." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114817/document.
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La variabilité pharmacocinétique liée à une élimination des médicaments par glucuronoconjugaison a été peu étudiée. Nous avons donc choisi d’étudier les caractéristiques pharmacocinétiques de deux médicaments glucuronoconjugués, l’acide mycophénolique (MPA, prodrogue, mycophénolate mofétil ou MMF) et le raltégravir, dans certaines situations cliniques spécifiques. Deux études cliniques ont été réalisées avec le MMF. En transplantation hépatique pédiatrique, des AUC0-12 de MPA supérieures à 30 mg.h/L ont été obtenues chez tous les enfants avec une dose de 600 mg/m² de MMF administrée par voie orale deux fois par jour. L’estimation de l’AUC0-12 par méthode non compartimentale étant particulièrement contraignante en pédiatrie, nous avons développé une stratégie de prélèvements limités permettant une estimation à partir de seulement trois prélèvements. Chez des patients adultes transplantés rénaux, nos travaux ont permis de caractériser le polymorphisme génétique des transporteurs ABCC2 et ABCB1 et l’albuminémie comme étant des facteurs de variabilité inter et intra-individuelle de la pharmacocinétique du MPA. Les concentrations intracellulaires moyennes de MPA dans les cellules mononuclées du sang périphérique étaient élevées et largement supérieures à la concentration de MPA inhibant 50% de l’activité de l’IMPDH. Nos premiers résultats concernant le raltégravir montrent que ses paramètres pharmacocinétiques sont caractérisés par une variabilité inter-individuelle importante chez des patients infectés par le VIH. Nous avons établi que le raltégravir ne se fixe pas du tout sur l’alpha-1-glycoprotéine acide mais se fixe à 60% sur l’albumine, cette fixation étant dépendante du pH plasmatique. Cependant, cette forte liaison du raltégravir à l’albumine n’empêche pas une bonne diffusion du médicament dans le compartiment séminal. En conclusion, les études de pharmacocinétique clinique que nous avons menées montrent que la variabilité de la pharmacocinétique de ces deux médicaments glucuronoconjugués est aussi importante que pour des médicaments métabolisés par le cytochrome P450 3A4. L’identification des facteurs de variabilité de ces médicaments contribue à l’optimisation des traitements<br>Pharmacokinetic variability was poorly studied for drugs eliminated by glucuronidation. We therefore chose to study the pharmacokinetic parameters of two glucuronidated drugs, mycophenolic acid (MPA, prodrug, mycophenolate mofetil or MMF) and raltegravir, in specific clinical situations. Two clinical studies were conducted with MMF. In pediatric liver transplantation, MPA AUC0-12 above the target AUC of 30 mg.h/L were obtained in all children with a MMF dosing regimen of 600 mg/m² administered orally twice a day. As extensive AUC monitoring is laborious, especially in children, we developed a limited sampling strategy to calculate MPA AUC0-12 with only three samples. In adult renal transplantation, our work allowed us to characterize genetic polymorphism of ABCC2 and ABCB1 genes and serum albumin as factors of inter and intraindividual variability in MPA pharmacokinetics. We demonstrated that MPA concentrations in peripheral blood mononuclear cells were high and well above the concentration of MPA responsible for a 50%-inhibition of the activity of IMPDH. Our first results show that the raltegravir pharmacokinetics is characterized by a wide interindividual variability in HIV-infected patients. Raltegravir does not bind to alpha-1-acid glycoprotein but binds to 60% to albumin and this binding is pH-dependent. Despite this high protein binding, a good penetration into the seminal compartment was evidenced. In conclusion, these clinical pharmacokinetic studies demonstrated that the variability in the pharmacokinetics of these glucuronidated drugs is as important as the one exhibited by drugs metabolized by cytochrome P450 3A4. Identifying factors of variability of these glucuronidated drugs contributes to optimizing patient care
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Bailly, François. "Optimisation du traitement anti-VHC : place des dosages pharmacologiques et des cinétiques virales à l'ère des antiviraux directs." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10328/document.
Full textAbstract:
Le traitement du VHC connaît une évolution rapide avec le développement d'antiviraux à action directe plus efficaces et mieux tolérés qui vont modifier les stratégies thérapeutiques, les facteurs prédictifs de réponse et les modalités de suivi des patients. Notre travail s'intéresse aux paramètres de suivi du traitement que sont les dosages pharmacologiques de ribavirine et le suivi des cinétiques virales lors d'une trithérapie. L'étude d'une cohorte prospective incluant 186 patients sous trithérapie par IP montre que 60% d'entre-eux présentent une SVR12 et que les facteurs prédictifs sont le génotype de l'IL28B et la réponse au précédent traitement. Une diminution de la filtration glomérulaire réversible est également observée. La mesure du taux résiduel de ribavirine permet de réduire les risques hématologiques chez des patients insuffisants rénaux, la réalisation de l'ASC témoigne d'une moins bonne exposition à la ribavirine chez des patients co-infectés par le VIH/VHC et la biodisponibilité de la ribavirine et la sévérité des anémies augmentent chez des patients traités par télaprévir. Au sein de la cohorte CUPIC, la négativation ou la diminution >50-70% de la charge virale initiale à S2 de trithérapie sont fortement prédictives de la SVR12. Cette mesure à S2 permet aussi de dépister les échappements viraux précoces. La place de la ribavirine est importante dans les associations thérapeutiques actuelles et futures. Sa surveillance pharmacologique peut avoir un intérêt au cours de futures multi-thérapies exposant à d'éventuelles interactions médicamenteuses<br>The rapid development of new direct antiviral agents (DAA) against HCV gives hope of more potent and well tolerated treatments. These new compounds will deeply modify therapeutic schedules, virological response prognostic factors and patients’ monitoring. The aim of our work was to define the relevance of ribavirin plasma concentration and viral kinetics monitoring during triple therapy. The study of a prospective cohort including 186 patients under triple therapy showed an SVR12 rate of 60%. Associated predictive factors were IL-28B genotype and previous treatment response. A reversible decrease of glomerular filtration rate was also observed. Ribavirin plasma concentration monitoring reduced hematological risks among patients with renal insufficiency. Early ribavirin plasma exposure showed an underexposure among HIV/HCV patients and ribavirin biodisponibility with severe anemia increased among telaprevir-treated patients. Within the CUPIC cohort, the initial viral load undetectability or decrease up to 50% or 70% at week 2 of triple therapy were predictive of SVR12. Moreover, this week 2 viral load assessment allowed the detection of early viral breakthrough. Ribavirin still plays a major role in current and future therapeutic strategies. Ribavirin monitoring could also be important during future multi-drug therapy that could be associated with drug interactions