Relevant bibliographies by topics / IVIVE

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  2. Dissertations / Theses
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Academic literature on the topic 'IVIVE'

Author: Grafiati
Published: 4 June 2021
Last updated: 1 February 2022

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Journal articles on the topic "IVIVE"

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Valdiviezo, Alan, Yu-Syuan Luo, Zunwei Chen, Weihsueh A. Chiu, and Ivan Rusyn. "Quantitative In Vitro-to-In Vivo Extrapolation for Mixtures: A Case Study of Superfund Priority List Pesticides." Toxicological Sciences 183, no. 1 (June 17, 2021): 60–69. http://dx.doi.org/10.1093/toxsci/kfab076.

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Abstract In vitro cell-based toxicity testing methods generate large amounts of data informative for risk-based evaluations. To allow extrapolation of the quantitative outputs from cell-based tests to the equivalent exposure levels in humans, reverse toxicokinetic modeling is used to conduct in vitro-to-in vivo extrapolation (IVIVE) from in vitro effective concentrations to in vivo oral dose equivalents. IVIVE modeling approaches for individual chemicals are well-established; however, the potential implications of chemical-to-chemical interactions in mixture settings on IVIVE remain largely unexplored. We hypothesized that chemical coexposures could modulate both protein binding efficiency and hepatocyte clearance of the chemicals in a mixture, which would in turn affect the quantitative IVIVE toxicokinetic parameters. To test this hypothesis, we used 20 pesticides from the Agency for Toxic Substances and Disease Registry Substance Priority List, both individually and as equimolar mixtures, and investigated the concentration-dependent effects of chemical interactions on in vitro toxicokinetic parameters. Plasma protein binding efficiency was determined by using ultracentrifugation, and hepatocyte clearance was estimated in suspensions of cryopreserved primary human hepatocytes. We found that for single chemicals, the protein binding efficiencies were similar at different test concentrations. In a mixture, however, both protein binding efficiency and hepatocyte clearance were affected. When IVIVE was conducted using mixture-derived toxicokinetic data, more conservative estimates of activity-to-exposure ratios were produced as compared with using data from single chemical experiments. Because humans are exposed to mixtures of chemicals, this study is significant as it demonstrates the importance of incorporating mixture-derived parameters into IVIVE for in vitro bioactivity data in order to accurately prioritize risks and facilitate science-based decision-making.
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Rostami-Hodjegan, Amin. "Principles in incorporating IVIVE into PBPK." Drug Metabolism and Pharmacokinetics 32, no. 1 (January 2017): S1. http://dx.doi.org/10.1016/j.dmpk.2016.10.009.

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Mallick, Pankajini. "Utilizing in vitro transporter data in IVIVE-PBPK: an overview." ADMET and DMPK 5, no. 4 (December 23, 2017): 201–11. http://dx.doi.org/10.5599/admet.5.4.441.

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In vitro-in vivo extrapolation (IVIVE) integrated in physiologically-based pharmacokinetic (PBPK) models have been increasingly used during drug discovery and development processes to predict human pharmacokinetic (PK) parameters. Drug transporters can influence drug pharmacokinetics and are key aspects contributing to the development of a successful drug. This review provides a snapshot of challenges or shortcomings of in vitro and in vivo techniques for understanding the contribution of drug transporters to a drug’s pharmacokinetics. The paper also describes the potential of IVIVE-PBPK models as prospective approaches to predict the role of drug transporters in drug discovery and development.
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Varma, Manthena V. "IVIVE of drug transporters and addressing challenges." Drug Metabolism and Pharmacokinetics 32, no. 1 (January 2017): S2. http://dx.doi.org/10.1016/j.dmpk.2016.10.012.

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Sinha, Jaydeep, Stephen B. Duffull, Bruce Green, and Hesham S. Al-Sallami. "Evaluating Lean Liver Volume as a Potential Scaler for In Vitro-In Vivo Extrapolation of Drug Clearance in Obesity Using the Model Drug Antipyrine." Current Drug Metabolism 21, no. 10 (December 15, 2020): 746–50. http://dx.doi.org/10.2174/1389200221666200515105800.

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Background : In vitro-in vivo extrapolation (IVIVE) of hepatic drug clearance (>CL) involves the scaling of hepatic intrinsic clearance (CLint,uH) by functional liver size, which is approximated by total liver volume (LV) as per the convention. However, in most overweight and obese patients, LV includes abnormal liver fat, which is not thought to contribute to drug elimination, thus overestimating drug CL. Therefore, lean liver volume (LLV) might be a more appropriate scaler of CLint,uH. Objective : The objective of this work was to assess the application of LLV in CL extrapolation in overweight and obese patients (BMI >25 kg/m2) using a model drug antipyrine. Methods: Recently, a model to predict LLV from patient sex, weight, and height was developed and evaluated. In order to assess the LLV model’s use in IVIVE, a correlation-based analysis was conducted using antipyrine as an example drug. Results : In the overweight group (BMI >25 kg/m2), LLV could describe 36% of the variation in antipyrine CL (R2 = 0.36), which was >2-fold higher than that was explained by LV (R2 = 0.17). In the normal-weight groupjats:(BMI ≤25 kg/m2), the coefficients of determination were 58% (R2 = 0.58) and 43% (R2= 0.43) for LLV and LV, respectively. Conclusion : The analysis indicates that LLV is potentially a more appropriate descriptor of functional liver size than LV, particularly in overweight individuals. Therefore, LLV has a potential application in IVIVE of CL in obesity.
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Lukacova, Viera. "Design and modelling of IVIVE for absorption studies." Drug Metabolism and Pharmacokinetics 32, no. 1 (January 2017): S1—S2. http://dx.doi.org/10.1016/j.dmpk.2016.10.010.

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Mallick, Pankajini, Marjory Moreau, Gina Song, Alina Y. Efremenko, Salil N. Pendse, Moire R. Creek, Thomas G. Osimitz, et al. "Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans." Toxicological Sciences 173, no. 1 (October 8, 2019): 86–99. http://dx.doi.org/10.1093/toxsci/kfz211.

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Abstract To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.
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Zou, Peng, Nan Zheng, Yanke Yu, Shanghai Yu, Wei Sun, Donna McEachem, Yongsheng Yang, Lawrence X. Yu, Shaomeg Wang, and Duxin Sun. "Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics." Journal of Pharmacy & Pharmaceutical Sciences 15, no. 2 (April 11, 2012): 265. http://dx.doi.org/10.18433/j34s4n.

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Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. Methods. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration–time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima’s method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration–time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h-1*kg-1. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg-1. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima’s transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Polli, James E. "IVIVR versus IVIVC." Dissolution Technologies 7, no. 3 (2000): 6–8. http://dx.doi.org/10.14227/dt070300p6.

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Tuszyński, Paweł Konrad, Sebastian Polak, Renata Jachowicz, and Aleksander Mendyk. "From in vitro-in vivo relationship (IVIVR) towards in vitro-in vivo extrapolation (IVIVE): A case study of pulmonary delivery systems." Dissolution Technologies 24, no. 4 (2017): 32–35. http://dx.doi.org/10.14227/dt240417p32.

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Dissertations / Theses on the topic "IVIVE"

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Da, Silva Franck. "Amélioration de la prédiction de la clairance métabolique via l’utilisation de modèles hépatiques innovants." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT083.

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La sélection des meilleurs candidats médicament se base sur des choix multiparamétriques réunissant l’efficacité potentielle, les caractéristiques ADME et le profil de sécurité des nouvelles entités chimiques. En ce sens, la prédiction précoce de la pharmacocinétique est élémentaire pour orienter les prises de décision et donner un cap pertinent aux projets. En raison de son rôle central dans le devenir des médicaments, la clairance métabolique médiée principalement par le foie est l’un des paramètres les plus importants. L’objectif de ce projet était d’améliorer la prédiction de la clairance en se concentrant notamment sur les molécules présentant une bonne stabilité métabolique et qui sont de ce fait encore difficiles à étudier. Les travaux menés dans cette thèse nous ont permis d’étoffer nos connaissances sur les modèles hépatiques in vitro et les méthodes d’extrapolation usuelles mais aussi de découvrir et de développer de nouvelles stratégies de prédiction. Nous nous sommes concentrés en profondeur sur la clairance métabolique et à tout ce qui impacte les prédictions. Le modèle de co-culture microorganisée (MPCC) HepatopacTM qui permet de stabiliser les hépatocytes humains sur plusieurs semaines a ainsi été identifié comme une alternative judicieuse aux modèles de routine lorsque les molécules ne peuvent pas être étudiées en culture 2D classique. L’étude de la fraction libre plasmatique et l’intégration de nouvelles hypothèses physiologiques telles que la théorie de « l’uptake facilité par l’albumine » ont également participé à améliorer les prédictions. Compte tenu des performances du modèle HepatopacTM, nous avons développé une approche innovante basée sur le spotting de précision afin de produire tous types de co-cultures microorganisées. Les co-cultures fabriquées grâce à cette technique démontrent que la méthode est robuste, accessible et simple à mettre en œuvre. Notre méthode de spotting a ensuite été utilisée pour faire évoluer le modèle MPCC et l’ouvrir à de nouvelles applications
The selection of the best drug candidates is based on multiparametric choices combining the potential efficacy, ADME characteristics and the safety profile of the new chemical entities. In this sense, the early prediction of pharmacokinetic is essential to guide decision-making and provide a relevant course for projects. Because of its central role in drug disposition, metabolic clearance mediated primarily by the liver is one of the most important parameters. The objective of this project was to improve clearance prediction by focusing on low clearance compounds that are still difficult to study. This work allowed us to expand our knowledge on in vitro liver models and usual extrapolation methods but also to discover and develop new prediction strategies. We focused on metabolic clearance and all parameters that impact the predictions. Micropatterned co-cultures (MPCCs) of primary human hepatocytes (HepatopacTM), which stabilizes hepatocytes over several weeks, has been identified as a judicious alternative to routine models when the molecules cannot be studied in conventional monolayer culture. The study of plasma protein binding and the integration of new physiological hypothesis such as the "Albumin-Facilitated Uptake" also contributed to improve the predictions. Given the performance of the HepatopacTM model, we have developed an innovative approach using a digital dispensing system to spot collagen and produce all types of micropatterned co-cultures. Co-cultures manufactured by this technique demonstrate that the method is robust, accessible and easy to use. Our spotting method was used to evolve the MPCC model and explore new applications
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Harwood, Matthew Dillston. "Towards a fully mechanistic prediction of oral drug absorption : investigating intestinal transporter abundance & function relationships." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/towards-a-fully-mechanistic-prediction-of-oral-drug-absorption-investigating-intestinal-transporter-abundance-and-function-relationships(a211b130-b8ac-4ce3-bf8f-728cf08df216).html.

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Background: Elucidating the role of intestinal drug transporter function in drug development is crucial, as transporter proteins can impact on drug absorption, efficacy and adverse events. In Vitro-In Vivo Extrapolation linked to Physiologically-Based Pharmacokinetic (IVIVE-PBPK) models aim to predict the in vivo impact of transporters from in vitro cell–based transport data and expression-based scaling factors. Currently, these models depend on relative measurements of transporter expression i.e., mRNA or immunoblotting. There is a critical need for physiologically relevant measures of transporter protein abundance to populate these biological frameworks. Objectives: The key objectives were to develop and validate a targeted proteomics workflow to quantify transporter protein abundances in human enterocytes and Caco-2 cells with a QconCAT technique. A cross-laboratory comparison on matched samples was also performed to assess between-laboratory bias in abundance determination. Together with abundance data from each laboratory, BCRP and P-gp transporter activities from Caco-2 cells were used to identify function-abundance relationships, to facilitate the potential development of abundance-function scaling factors. Results: Development of a differential centrifugation technique to obtain plasma membranes was undertaken using MDCK-II and Caco-2 cells. The plasma membrane fraction showed little enrichment from the preceding total membrane fraction and was contaminated with endoplasmic reticulum, as assessed by marker enzyme activities. There were also no differences in Na/K-ATPase, BCRP and P-gp abundances between plasma and total membrane fractions in Caco-2 cells. This may be due to losses of protein from the target membrane fraction, thus, a theoretical framework combining protein assay (BCA) and transporter abundance determinations was proposed. Pilot data on the generation of recovery correction factors using Villin and Na/K-ATPase abundances, to account for protein losses is also presented. The abundances of 6 transporters in jejunal enterocyte membranes (n=3), including the key efflux proteins BCRP (2.56±0.82 fmol/μg), P-gp (1.89±1.07 fmol/μg) and MRP2 (0.59±0.246 fmol/μg) were determined with precision. In addition, peptide losses during protein digestion stages were accounted for in abundance determinations. A cross laboratory comparison of transporter abundances from intestinal (n=4) and Caco-2 cells (n=7) measured in our laboratory and Bertin Pharma (BPh), showed that P-gp abundances were highly correlated (rs=0.72), yet BPh abundances were systematically lower than determined in our laboratory (2.0±2.08 versus. 4.8±3.51 fmol/μg, respectively). No differences or correlations were found for Na/K-ATPase and BCRP abundances between laboratories. A jejunal-Caco-2 cell relative expression factor (REF) for each protein for both laboratories was generated. The P-gp REF was similar for BPh and our laboratory (0.37 vs. 0.4, respectively) however, for BCRP there was a distinct difference (1.11 versus 2.22, respectively). These findings provide the first evidence that employing expression factors generated from abundances quantified in different laboratories may produce altered IVIVE-PBPK outcomes. Functional studies in Caco-2 cells using E-3-S and vinblastine as probes for BCRP and P-gp, respectively, show that protein abundance is more closely correlated to transporter activity than mRNA expression. In addition, it was only possible to verify that increasing P-gp abundances in Caco-2 cells were ranked alongside vinblastine intrinsic clearance, as there was little consistency when estimating Km between the different Caco-2 cell models expressing increasing P-gp abundances, which may be attributed to limited absorptive transport saturation. Thus, forming any conclusions with confidence on concentration dependent abundance-activity relationships was difficult. These data suggest the value of REF scaling factors based on protein abundances, but emphasises the need to generate these from both in vitro and in vivo samples, using the same proteomic workflow. Further work to verify abundance-function relationships is required. Conclusion: A targeted proteomic workflow has been developed allowing quantification of protein abundances for key drug transporters in human gut tissues and cell models. The study has highlighted important areas including losses of targeted proteins, contamination of plasma membrane fractions and standardisation between laboratories that need to be addressed before implementation of transporter abundances into PBPK models is undertaken. Nevertheless, the evidence for a close relationship between transporter abundance and function indicate the potential value of this data for generation of robust REF scaling factors.
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Maharao, Neha V. "Inhibition of Oxidative and Conjugative Metabolism of Buprenorphine Using Generally Recognized As Safe (GRAS) Compounds or Components of Dietary Supplements." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4752.

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This dissertation aimed at developing an inhibitor strategy to improve the oral bioavailability (Foral) and systemic exposure (AUC∞) of buprenorphine (BUP) as well as reduce the variability associated with them. Twenty-seven generally recognized as safe (GRAS) compounds or dietary substances were evaluated for their potential to inhibit the oxidative and conjugative metabolism of BUP, using pooled human intestinal and liver microsomes. In both the organs, oxidation appeared to be the major metabolic pathway with a 6 fold (intestine) and 4 fold (liver) higher intrinsic clearance than glucuronidation. Buprenorphine was predicted to show low and variable Foral, AUC∞, and a large total clearance. The biorelevant solubilities of 5 preferred inhibitors were incorporated in the final model. An inhibitor dosing strategy was identified to increase Foral and reduce the variability in oral BUP AUC∞. These results demonstrate the feasibility of the approach of using GRAS or dietary compounds to inhibit the presystemic metabolism of buprenorphine and thus improve its oral bioavailability. This inhibitor strategy has promising applicability to a variety of drugs suffering from low and variable oral bioavailability due to extensive presystemic oxidative and conjugative metabolism.
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Reddyhoff, Dennis. "Mathematical modelling of acetaminophen induced hepatotoxicity." Thesis, Loughborough University, 2016. https://dspace.lboro.ac.uk/2134/23008.

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Acetaminophen, known as paracetamol in the UK and Tylenol in the United States, is a widespread and commonly used painkiller all over the world. Taken in large enough doses, however, it can cause fatal liver damage. In the U.S., 56000 people are admitted to hospital each year due to acetaminophen overdose and its related effects, at great cost to healthcare services. In this thesis we present a number of different models of acetaminophen metabolism and toxicity. Previously, models of acetaminophen toxicity have been complex and due to this complexity, do not lend themselves well to more advanced mathematical analysis such as the perturbation analysis presented later in this thesis. We begin with a simple model of acetaminophen metabolism, studying a single liver cell and performing numerical and sensitivity analysis to further understand the most important mechanisms and pathways of the model. Through this we identify key parameters that affect the total toxicity in our model. We then proceed to perform singular perturbation analysis, studying the behaviour of the model over different timescales, finding a number of key timescales for the depletion and subsequent recovery of various cofactors as well as critical dose above which we see toxicity occurring. Later in the thesis, this model is used to model metabolism in a spheroid cell culture, examining the difference spatial effects have on metabolism across a 3D cell culture. We then present a more complex model, examining the difference the addition of an adaptive response to acetaminophen overdose from the Nrf2 signalling pathway, has on our results. We aim to reproduce an unexplained result in the experimental data of our colleagues, and so analyse the steady states of our model when subjected to an infused dose, rather than a bolus one. We identify another critical dose which leads to GSH depletion in the infused dose case and find that Nrf2 adaptation decreases toxicity and model sensitivity. This model is then used as part of a whole-body PBPK model, exploring the effects that the distribution of the drug across the bloodstream and different organs has. We explore the affects of that a delay in up-regulation from the Nrf2 pathway has on the model, and find that with rescaled parameters we can qualitatively reproduce the results of our collaborators. Finally, we present the results of in vitro work that we have undertaken, the aim of which was to find new parameters for the model in human hepatocytes, rather than from rodent models, and find a new value for a parameter in our model from human cell lines.
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Leding, Albin. "Recommendation for first pharmacokinetic in vivo experiment design with a pharmacometric informed approach." Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-447311.

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Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.
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Leding, Albin. "Optimized design recommendation for first pharmacokinetic in vivo experiments for new tuberculosis drugs using pharmacometrics modelling and simulation." Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-447311.

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Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.
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Emuekpere-Masagbor, Grace Aboshuogwe. "Preverbal subject markers in Ivie, Les marqueurs de sujet préverbaux en ivié." Thèse, Université de Sherbrooke, 1997. http://savoirs.usherbrooke.ca/handle/11143/2683.

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The goal of this study is to investigate the properties and functions of preverbal subject markers in Ivie. Ivie like most African languages and Romance languages, has features that indicate number in both verbs and nouns, gender and case in nouns, and person in verbs. In Romance languages such as French and Italian, information about these features is normally given by verbal desinences which are invariably suffixed to such verbs. These desinences realized on verbs indicate person and number. In Ivie, these same features (number and person) are marked on the verb in form of preverbal subject markers which occur between the nominal subject and the verb. Their presence is obligatory in all Ivie sentences. This thesis discusses these preverbal subject markers with a view to determining their grammatical status in the language.The descriptions of these elements are based on some assumptions of the Checking Theory within the Minimalist Framework (Chomsky 1993, 1995), together with ideas from other applicable theories. In the literature, similar grammatical elements have been variously described as clitics, incorporated pronouns and agreement markers. In languages like Quebec French (Roberge 1990), the Northern Italian dialects of Trentino and Fiorentino (Brandi and Cordin 1989) among others, it has been argued that sentences containing noun phrases together with these elements instantiate the phenomenon of subject doubling. Ivie seems to exemplify this phenomenon in view of the obligatory presence of preverbal pronominal elements with subject phrases in all Ivie grammatical constructions. In this work, a number of questions related to the properties and functional roles of the subject markers are elucidated. In particular, we showed that they are not clitic pronouns but rather agreement morphemes necessary between subjects and their verbs due to the lack of overt inflection on Ivie verbs. Drawing on theoretical foundation from morphology, syntax and phonology, as well as analogy and comparison from similar processes in many other languages, we showed that: (i) Ivie subject markers represent subject-verb agreement; and (ii) they are neither weak nor clitic pronouns since they are never in complementary distribution with Determiner phrases (DPs). This fact is further strengthened by the presence of pro when subjects are dropped in sentences. This evidence also shows that subject markers are realized in non-argumental positions in Ivie. In addition, our analysis indicates that only independent subject pronouns are attested in the language. Therefore, there is no basis to label the preverbal subject markers as weak or clitic pronoun as no overt dependent subject pronoun exists in the language. We have shown that subject markers are nothing but manifestations of subject-agreement in the language. Aside from subject-verb agreement, agreement is also triggered in a variety of other contexts in the language.
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Dong, Jin. "First-principle based pharmacokinetic modeling." Scholarly Commons, 2016. https://scholarlycommons.pacific.edu/uop_etds/128.

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Predicting drug concentrations in the blood and at the site of action is the hottest topic in pharmacokinetics (PK). In vitro-in vivo extrapolation (IVIVE) and physiological based pharmacokinetics (PBPK) models are two major PK prediction strategies. However, both IVIVE and PBPK models are considered as immature methodologies due to their poor predictability. The goal of the research is to investigate the discrepancies within IVIVE and PBPK predictions according to first-principles: convection, diffusion, metabolism, and carrier-mediated transport. In Chapter 2, non-permeability limited hepatic elimination under perfusion steady state is examined. The well-stirred model is re-derived from the convection-dispersion-elimination equation when both dispersion and concentration gradient are ignored and re-named as the zero-gradient model. Pang and Rowland’s lidocaine data are re-analyzed. Their data analysis was based on an unfair comparison of the zero-gradient and parallel- tube models at two different efficiency number ranges. The interference of sensitivity greatly biased the comparison. I also show that both theoretical discussions and experimental results indicate that apparent intrinsic clearance and intrinsic clearance could be affected by blood flow and protein binding. In Chapter 3, I discuss permeability limited hepatic elimination under perfusion steady state. Permeability limited elimination is classified to diffusion dominated, carrier-mediated transport mediated, and mixed effects based on drug passage mechanisms. Each of these three drug passage classes is sub-divided to sink condition and finite volume condition based on the boundary conditions of drug passage. In Chapter 4, the discrepancies within IVIVE for both non-permeability limited and permeability limited drugs are explored. The deficiencies in assay design and data analysis of common in vitro metabolism assays are investigated. The scaling/converting equations for both non-permeability limited and permeability limited drugs are derived. In Chapter 5, I focus on transient PK models. Numerical analysis using finite difference and finite volume methods are introduced into the derivation and discussion of transient PBPK models. In addition, the use of partition coefficient in the non-eliminating tissue/organ models is discussed.
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Wingert, Nathalie Ribeiro. "Desenvolvimento e validação de métodos analíticos e estudos de estabilidade da rivaroxabana." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/149500.

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A análise de fármacos é fundamental nas diversas fases do desenvolvimento farmacêutico, tais como estudos de formulação, estabilidade e controle de qualidade do produto. A rivaroxabana (RIV) é um anticoagulante de uso oral indicado para prevenção da formação de coágulos venosos. A literatura pesquisada apresenta poucos relatos de determinação quantitativa e de estudos de estabilidade do fármaco em comprimidos. E ainda nenhum método analítico em compêndios oficiais Diante do exposto, o objetivo deste trabalho foi desenvolver e validar métodos analíticos para determinação qualitativa e quantitativa da RIV por cromatografia líquida de alta eficiência com detecção por UV e de ultra eficiência com detecção por espectrometria de massas (CLAE-UV e CLUE-EM) e eletroforese capilar (EC). Os resultados encontrados foram adequados conforme o preconizado nos guias oficiais nacionais e internacionais. Foi avaliada também a viabilidade da técnica de eletroforese capilar em microchip para análise de RIV. Através de método desenvolvido por CLAE foi realizado estudo de cinética de degradação e posterior avaliação do potencial tóxico in vitro das amostras de degradação forçada da RIV. A identificação de três produtos de degradação majoritários da RIV, formados a partir de estresse ácido, alcalino e fotolítico, foi realizada por CLUE-EM/EM, possibilitando a proposição da estrutura molecular de cada produto de degradação. O potencial tóxico da RIV antes e depois da exposição à degradação forçada foi avaliado através dos métodos in vitro MTT, Vermelho Neutro, Ensaio Cometa e DNA de baixo peso molecular. Não foram encontrados sinais de dano ao DNA celular, contudo, amostras de RIV expostas ao meio alcalino apresentaram maior redução da viabilidade celular. O trabalho avaliou ainda o perfil de dissolução da RIV em comprimidos baseado nos dados de absorção in vitro conforme modelagem in silico dos dados, estabelecendo uma correlação linear entre a fração absorvida e fração dissolvida. As diferentes metodologias e técnicas desenvolvidas e aplicadas nesse trabalho contribuem para o desenvolvimento do controle de qualidade farmacêutico na direção de ensaios mais confiáveis que garantam a segurança e eficácia de medicamentos.
Drug analysis is critical at various stages of pharmaceutical development, such as formulation studies, stability and quality control products. Rivaroxaban (RIV) is an oral anticoagulant indicated for prevention of thromboembolism. Literature contains few reports of quantitative determination and drug stability studies of RIV on pharmaceutical formulation. Analytical method for RIV quality control are not evaluable on official guides yet. This research work aimed to develop and validate analytical methods for qualitative and quantitative determination of RIV by high and ultra performance liquid chromatography with UV detection mass spectrometry detection (HPLC -UV and UPLC-MS) and capillary electrophoresis (CE). The results were adequate as recommended in national and international official guides. Reliability of RIV analysis by microchip capillary electrophoresis was also assessed. Through the method developed by HPLC degradation kinetic studies were performed, zero order kinetic has better description of RIV degradation behaviour. RIV toxic potential before and after exposure to forced degradation was assessed by in vitro methods of MTT, Neutral Red, Comet Assay, and Low Molecular Weight DNA. There were no signals of DNA damage however, RIV samples exposed to alkaline medium showed increased reduction in cell viability. Identification of RIV degradation products formed after exposure to acid and alkaline media and UVC radiation was performed by UPLC-MS / MS. It was possible to elucidate molecular structures of three major degradation products. This study also assessed the dissolution profile of RIV tablets based on in vitro absorption data, a linear point-to-point correlation was found for fraction absorbed and dissolved. Different methodologies and techniques developed and applied in this work can contribute to the development of pharmaceutical quality towards more reliable tests to ensure safety and efficacy of medicines.
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Richards, Katie Kristina. "Fremont Ceramic Designs and Their Implications." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/4203.

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Although Fremont ceramic design styles have the potential to tell archaeologists a great deal about Fremont social interaction and boundaries, they have never been studied in detail. In the Fremont world, painted designs appear almost exclusively on the inside of bowls produced in two different regions of Utah. The firstis the Snake Valley production zone in southwestern Utah where Snake Valley Black-on-gray was produced; the second is the Emery production zone in central Utah where white-slipped Ivie Creek Black-on-white bowls were produced. The similarities in designs on the two main types of Fremont painted bowls indicates regional interaction and exchange of both materials and ideas between the two production zones, while the differences suggest regional distinctions existed within a larger Fremont complex.
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Books on the topic "IVIVE"

1

Jevtić, Miloš. Ognjište Ivice Mlađenovića. Beograd: Beogradska knjiga, 2001.

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Patmarājan, Pi. Itā, iviṭe vare. 2nd ed. Kōl̲ikkōṭ: Pūrṇa Pabḷikkēṣans, 1994.

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Čuvari kazačke ivice. Beograd: Narodna knj. Alfa, 2002.

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Candramati. Iviṭe oru ṭekki. [Kottayam]: Ḍi. Si. Buks, 2010.

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Čuvari kazačke ivice: Roman. Beograd: Radio B92, 1997.

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Braunová, Petra. Kamila Moučková: Nejsem žádná Ivice : životní příběh legendární hlasatelky. Praha: 65. pole, 2010.

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Evans, Len. The Ivie family of Utah: An American migration, 1800-1900. [Ventura, CA] (289 1/2 Harrison Ave., Ventura, 93001): L. Evans, 1998.

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Ivie, Tom. Patton's eyes in the sky: USAAF combat reconnaissance missions : north-west Europe 1944-1945 / Tom Ivie. Hersham: Classic Publications, 2003.

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Srpska akademija nauka i umetnosti. Odeljenje hemijskih i bioloških nauka., ed. Mravi Srbije i Crne Gore: Primljeno na IV skupu Odeljenja hemijskih i bioloških nauka od 23. juna 2006. godine na osnovu referata dopisnog člana Marka Anđelkovića, akademika Gordana Karamana (Canu) i prof. Dr Ivice Radovića. Beograd: Srpska akademija nauka i umetnosti, 2006.

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Nolan, Francis, and Brechtje Post. The IViE Corpus. Oxford University Press, 2013. http://dx.doi.org/10.1093/oxfordhb/9780199571932.013.025.

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Book chapters on the topic "IVIVE"

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Balogh, Larissa M., and Yurong Lai. "Applications of Targeted Proteomics in ADME for IVIVE." In Transporters in Drug Development, 99–119. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-8229-1_5.

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Rostami-Hodjegan, Amin. "Translation of In Vitro Metabolic Data to Predict In Vivo Drug–Drug Interactions: IVIVE and Modeling and Simulations." In Enzyme- and Transporter-Based Drug-Drug Interactions, 317–41. New York, NY: Springer New York, 2009. http://dx.doi.org/10.1007/978-1-4419-0840-7_13.

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Devane, John. "Impact of IVIVR on Product Development." In Advances in Experimental Medicine and Biology, 241–59. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4684-6036-0_23.

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Sathe, Pradeep, Yi Tsong, and Vinod P. Shah. "in Vitro Dissolution Profile Comparison and IVIVR." In Advances in Experimental Medicine and Biology, 31–42. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4684-6036-0_3.

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Dunne, Adrian, Tom O’Hara, and John Devane. "Approaches to IVIVR Modelling and Statistical Analysis." In Advances in Experimental Medicine and Biology, 67–86. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4684-6036-0_6.

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Malinowski, Henry J. "The Role of in Vitro-in Vivo Correlations (IVIVC) to Regulatory Agencies." In Advances in Experimental Medicine and Biology, 261–68. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4684-6036-0_24.

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"Study Design Considerations for IVIVC Studies." In Pharmaceutical Dissolution Testing, 299–332. CRC Press, 2005. http://dx.doi.org/10.1201/9780849359170-13.

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Farrell, Colm, Myriam Rochdi, and Theresa Shepard. "Study Design Considerations for IVIVC Studies." In Pharmaceutical Dissolution Testing, 281–313. Informa Healthcare, 2005. http://dx.doi.org/10.1201/9780849359170.ch10.

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Locke, John. "113 LOCKE to DR. AYLIFFE IVIE, 8 January [1661?] (97)." In The Clarendon Edition of the Works of John Locke: The Correspondence of John Locke: In Eight Volumes, Vol. 1: Introduction; Letters Nos. 1–461, edited by E. S. de Beer, 166. Oxford University Press, 2010. http://dx.doi.org/10.1093/oseo/instance.00020742.

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Farrell, Colm, and Siobhan Hayes. "IVIVC for Oral Drug Delivery: Immediate Release and Extended Release Dosage Forms." In Pharmaceutical Product Development, 125–39. CRC Press, 2007. http://dx.doi.org/10.3109/9781420020175-6.

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Conference papers on the topic "IVIVE"

1

Stefanović, Hana, Svetlana Štrbac-Savić, and Dejan Milić. "Poređenje performansi različitih metoda detekcije ivice u digitalnoj slici." In Synthesis 2015. Belgrade, Serbia: Singidunum University, 2015. http://dx.doi.org/10.15308/synthesis-2015-123-128.

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Gao, M. M., R. P. Xu, and T. Sun. "A method for multi-attribute decision making based on TOPSIS and IVIFE." In International Conference on Computer Science and Systems Engineering. Southampton, UK: WIT Press, 2015. http://dx.doi.org/10.2495/csse140181.

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Reports on the topic "IVIVE"

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Benages, Eva, and Matilde Mas. Knowledge-Based Capital in a Set of Latin American Countries: The LA KLEMS-IADB Project. Inter-American Development Bank, April 2021. http://dx.doi.org/10.18235/0003202.

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This paper presents the framework and methodology for the economic valuation of the knowledge-based economy in five Latin American (LA) countries, namely Costa Rica, El Salvador, Mexico, Peru and the Dominican Republic, for which a new database (IDB-Ivie, 2020) has recently been released. It uses an alternative approach to measuring the knowledge intensity of economies as to those based on the aggregation of industries according to selected indicators such as research and development (R&D) expenditure or labor force skills. Instead, we follow an economic approach rooted in the growth accounting methodology, determining the contribution of each individual factor of production (capital and labor) according to the prices of the services it provides. This methodology will be applied to the above-mentioned LA countries, and to the United States and Spain, which are used as benchmarks. Data are available for the period 1995-2016.
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