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Journal articles on the topic 'Preclinical PK'

Author: Grafiati

Published: 2 June 2025

Last updated: 31 July 2025

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1

Hosseini, Iraj, Brett Fleisher, Jennifer Getz, et al. "A Minimal PBPK/PD Model with Expansion-Enhanced Target-Mediated Drug Disposition to Support a First-in-Human Clinical Study Design for a FLT3L-Fc Molecule." Pharmaceutics 16, no. 5 (2024): 660. http://dx.doi.org/10.3390/pharmaceutics16050660.

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FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically based PK/PD model with expansion-enhanced target-mediated drug disposition (TMDD) was developed to integrate the molecule’s mechanism of action, as well as the complex preclinical and clinical PK/PD data, to support the preclinical-to-clinical translation of FLT

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Heller, A. A., S. Y. Lockwood, T. M. Janes, and D. M. Spence. "Technologies for Measuring Pharmacokinetic Profiles." Annual Review of Analytical Chemistry 11, no. 1 (2018): 79–100. http://dx.doi.org/10.1146/annurev-anchem-061417-125611.

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The creation of a pharmacokinetic (PK) curve, which follows the plasma concentration of an administered drug as a function of time, is a critical aspect of the drug development process and includes such information as the drug's bioavailability, clearance, and elimination half-life. Prior to a drug of interest gaining clearance for use in human clinical trials, research is performed during the preclinical stages to establish drug safety and dosing metrics from data obtained from the PK studies. Both in vivo animal models and in vitro platforms have limitations in predicting human reaction to a

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Ge, Yun-Xuan, Zhuo Zhang, Jia-Yi Yan, et al. "Prediction of Human Pharmacokinetics of E0703, a Novel Radioprotective Agent, Using Physiologically Based Pharmacokinetic Modeling and an Interspecies Extrapolation Approach." International Journal of Molecular Sciences 25, no. 5 (2024): 3047. http://dx.doi.org/10.3390/ijms25053047.

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E0703, a new steroidal compound optimized from estradiol, significantly increased cell proliferation and the survival rate of KM mice and beagles after ionizing radiation. In this study, we characterize its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. The preclinical PK of E0703 was studied in mice and Rhesus monkeys. Asian human clearance (CL) values for E0703 were predicted from various allometric methods. The human PK profiles of E0703 (30 mg) were predicted by the PBPK model in Gastro Plus software 9.8 (SimulationsPl

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Na, Joo Young, Min Hai, Kyeongmin Kim, et al. "Translational Pharmacokinetic-Pharmacodynamic Modeling of a Novel Oral Dihydroorotate Dehydrogenase (DHODH) Inhibitor, HOSU-53 (JBZ-001)." Pharmaceutics 17, no. 4 (2025): 412. https://doi.org/10.3390/pharmaceutics17040412.

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Background: HOSU-53 (JBZ-001), an orally bioavailable new chemical entity, represents a highly potent dihydroorotate dehydrogenase (DHODH) inhibitor in late preclinical development for application in cancer therapy. Methods: Multiple Good Laboratory Practice (GLP) and non-GLP preclinical studies were conducted in mice, rats, and dogs. Plasma samples of HOSU-53 and dihydroorotate (DHO), the substrate of DHODH, were collected for pharmacokinetic (PK) and pharmacodynamic (PD) assessment and modeling. Two modeling approaches were utilized to understand the PK/PD properties of HOSU-53 and to recomm

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Wang, Yang, Lu Zhang, Shuang Gu, et al. "The Current Application of LC-MS/MS in Pharmacokinetics of Traditional Chinese Medicines (Recent Three Years): A Systematic Review." Current Drug Metabolism 21, no. 12 (2020): 969–78. http://dx.doi.org/10.2174/1389200221666201009142418.

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Background: With significant clinical effects, traditional Chinese medicine (TCM) has been attracting increasing interest of the world’s scientific community. However, TCM contains immense amounts of chemical components. It is a great challenge to objectively evaluate the correlation between the in vivo process and the therapeutic effect of TCM. The purpose of this systematic review was to summarize the recent investigation (from 2017 to 2019) on preclinical pharmacokinetics (PK) of TCM via liquid chromatography coupled with mass spectrometry (LC-MS/MS). Method: We reviewed the published artic

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Patel, Chirag G., Mayank Patel, Arijit Chakravarty, et al. "Clinical pharmacokinetics (PK) and translational PK-pharmacodynamic (PD) modeling and simulation to predict antitumor response of various dosing schedules to guide the selection of a recommended phase II dose (RP2D) and schedule for the investigational agent MLN0128." Journal of Clinical Oncology 31, no. 15_suppl (2013): 2567. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2567.

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2567 Background: MLN0128 (INK128) is an investigational oral, potent, and highly selective inhibitor of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) currently in clinical investigation. In the phase1 study INK128-001, MLN0128 was administered once daily (QD), once weekly (QW), QDx3D/week, and QDx5D/week, with respective MTDs of 6, 40, 16, and 10 mg. To guide selection of dose/schedule for further investigation, PD modulation in skin (pS6, p4EBP1, pNDRG1, pPRAS40) was put into context of clinical PK in INK128-001. A preclinical translational dynamic-PK efficacy model was used to des

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Cheng, Shen, Susheel Kumar Nethi, Mahmoud Al-Kofahi, and Swayam Prabha. "Pharmacokinetic—Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells." Pharmaceutics 13, no. 1 (2021): 92. http://dx.doi.org/10.3390/pharmaceutics13010092.

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Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) are efficacious in treating lung and ovarian tumors in mouse models. The quantitative description of pharmacokinetics (PK) and pharmacodynamics (PD) of nano-MSCs is crucial for optimizing their therapeutic efficacy and clinical translatability. However, successful translation of nano-MSCs is challenging due to their complex composition and physiological mechanisms regulatin

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Pasipanodya, Jotam, and Tawanda Gumbo. "An Oracle: Antituberculosis Pharmacokinetics-Pharmacodynamics, Clinical Correlation, and Clinical Trial Simulations To Predict the Future." Antimicrobial Agents and Chemotherapy 55, no. 1 (2010): 24–34. http://dx.doi.org/10.1128/aac.00749-10.

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ABSTRACTAntimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were

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Singh, Dharaminder, Sudhir P. Deosarkar, Elaine Cadogan, et al. "A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models." PLOS Biology 20, no. 5 (2022): e3001624. http://dx.doi.org/10.1371/journal.pbio.3001624.

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Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its abi

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10

Liu, Bo, Jonathan Chang, William P. Gordon, John Isbell, Yingyao Zhou, and Tove Tuntland. "Snapshot PK: a rapid rodent in vivo preclinical screening approach." Drug Discovery Today 13, no. 7-8 (2008): 360–67. http://dx.doi.org/10.1016/j.drudis.2007.10.014.

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11

Lindhardt, Emma, and Peter Gennemark. "Automated analysis of routinely generated preclinical pharmacokinetic and pharmacodynamic data." Journal of Bioinformatics and Computational Biology 12, no. 03 (2014): 1450010. http://dx.doi.org/10.1142/s0219720014500103.

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Model-based analysis of routinely generated pharmacokinetic and pharmacodynamic (PK–PD) data is a key component of preclinical drug discovery. The work process of such analyses can be automated by properly designed computer programs that reduce the number of manual steps, resulting in time saving and significantly fewer errors. Critical decisions can still be made by modelers. Using concrete animal data examples this paper illustrates when, and demonstrates how, automated PK–PD approaches can be used and what benefits they offer to the modeling and simulation community. Specifically, we descri

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Rychahou, Piotr G., Aman Chauhan, Zeta Chow, et al. "Abstract 3585: DNA-PK inhibition to enhance radiation sensitivity in metastatic pancreatic neuroendocrine cancer." Cancer Research 84, no. 6_Supplement (2024): 3585. http://dx.doi.org/10.1158/1538-7445.am2024-3585.

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Abstract Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are neoplasms originating from the gastrointestinal track and pancreas. Unfortunately, most patients at the time of diagnosis have extensive metastatic disease and are not candidates for curative surgical resection of metastatic tumors. In such cases, targeted radiation therapy (RT) can slow the progression of metastatic disease, but eventually tumors develop resistance to radiation therapy. In this study, we examined whether DNA-PK inhibition could sensitize pancreatic NETs to radiation therapy and enhance the radiation therap

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13

Li, Chao, Lowell Hart, Taofeek K. Owonikoko, et al. "Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer." Cancer Chemotherapy and Pharmacology 87, no. 5 (2021): 689–700. http://dx.doi.org/10.1007/s00280-021-04239-9.

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Abstract Purpose Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). Methods A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 b

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14

Zheng, Ying, Guifang Dou, Shuchen Liu, et al. "Preclinical Pharmacokinetics and Biodistribution of LR004, a Novel Antiepidermal Growth Factor Receptor Monoclonal Antibody." Molecules 29, no. 2 (2024): 545. http://dx.doi.org/10.3390/molecules29020545.

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LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonline

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Zalba, Sara, Ana M. Contreras-Sandoval, Eva Martisova, Reno Debets, Christian Smerdou, and María Jesús Garrido. "Quantification of Pharmacokinetic Profiles of PD-1/PD-L1 Antibodies by Validated ELISAs." Pharmaceutics 12, no. 6 (2020): 595. http://dx.doi.org/10.3390/pharmaceutics12060595.

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Immunotherapy has changed the paradigm of cancer treatments. In this way, several combinatorial strategies based on monoclonal antibodies (mAb) such as anti (a)-PD-1 or anti (a)-PD-L1 are often reported to yield promising clinical benefits. However, the pharmacokinetic (PK) behavior of these mAbs is a critical issue that requires selective analytical techniques. Indeed, few publications report data on a-PD1/a-PD-L1 exposure and its relationship with therapeutic or toxic effects. In this regard, preclinical assays allow the time profiles of antibody plasma concentrations to be characterized rap

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Burke, John M., Anna Katharina Wilkins, Andrew Matteson, Lore Gruenbaum, and Josh F. Apgar. "Computational exploration of mechanistic determinants of antibody drug-conjugate pharmacokinetics using quantitative systems pharmacology modeling strategies." Journal of Clinical Oncology 35, no. 15_suppl (2017): e14000-e14000. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e14000.

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e14000 Background: The pharmacokinetics of antibody drug conjugate (ADC) therapeutics typically show a discrepancy between the PK of total antibody (conjugated and unconjugated antibody) and that of conjugated antibody, carrying one or more payload molecules This discrepancy is often attributed to deconjugation (Kamath, 2014), however recent evidence suggests that the underlying mechanisms may be more complex. Methods: This work employs a computational quantitative systems pharmacology (QSP) approach to understand the impact of drug antibody ratio (DAR) and the resulting changes in molecular p

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Howard, Alex, and William Hope. "Assessment of Antifungal Pharmacodynamics." Journal of Fungi 9, no. 2 (2023): 192. http://dx.doi.org/10.3390/jof9020192.

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Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This review details the last 30 years of progress in terms of disease model design, efficacy outcome selection and translational modelling in antifungal PK-PD studies. The principles of how PK-PD parameters inform current clinical practice are also discussed, including a review of how these apply to existing and novel agen

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Robarge, Jason D., Kevin M. Budge, Lucy Her, Andrea M. Patterson, and Patricia Brown-Augsburger. "Rat as a Predictive Model for Human Clearance and Bioavailability of Monoclonal Antibodies." Antibodies 14, no. 1 (2024): 2. https://doi.org/10.3390/antib14010002.

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Background: The prediction of human clearance (CL) and subcutaneous (SC) bioavailability is a critical aspect of monoclonal antibody (mAb) selection for clinical development. While monkeys are a well-accepted model for predicting human CL, other preclinical species have been less-thoroughly explored. Unlike CL, predicting the bioavailability of SC administered mAbs in humans remains challenging as contributing factors are not well understood, and preclinical models have not been systematically evaluated. Methods: Non-clinical and clinical pharmacokinetic (PK) parameters were mined from public

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Shi, Rong, Shengchao Lin, Yu Zhang, Bing Li, Haiqing Hua, and Yang Qiu. "Abstract 2793: Preclinical pharmacokinetics in cynomolgus monkeys and first in human dose prediction of DB-1303, a HER2-targeting antibody-drug conjugate." Cancer Research 83, no. 7_Supplement (2023): 2793. http://dx.doi.org/10.1158/1538-7445.am2023-2793.

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Abstract Background: DB-1303 is a novel antibody-drug conjugate comprised of trastuzumab biosimilar, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have high plasma stability, low free payload in circulation and wide therapeutic index. Herein, the preclinical pharmacokinetics (PK) characteristics of DB-1303 in cynomolgus monkeys is reported, and human PK exposure in a first in human study was predicted using population PK model with allometric scaling. Material and Methods: The PK parameters of DB-1303 were obtained from single PK a

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Chen, Dapeng. "Targeted Protein Degraders (TPD): PK/PD translation from preclinical to clinical." Drug Metabolism and Pharmacokinetics 61 (June 2025): 101085. https://doi.org/10.1016/j.dmpk.2025.101085.

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21

Drusano, G. L., S. L. Preston, C. Hardalo, et al. "Use of Preclinical Data for Selection of a Phase II/III Dose for Evernimicin and Identification of a Preclinical MIC Breakpoint." Antimicrobial Agents and Chemotherapy 45, no. 1 (2001): 13–22. http://dx.doi.org/10.1128/aac.45.1.13-22.2001.

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ABSTRACT One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial agents is dose selection. The choice is often based on preclinical data from pharmacokinetic (PK) studies with animals and healthy volunteers but is rarely linked directly to the target organisms except by the MIC, an in vitro measure of antimicrobial activity with many limitations. It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model which uses four data sets: (i) t

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Gautam, Nagsen, Upal Roy, Shantanu Balkundi, et al. "Preclinical Pharmacokinetics and Tissue Distribution of Long-Acting Nanoformulated Antiretroviral Therapy." Antimicrobial Agents and Chemotherapy 57, no. 7 (2013): 3110–20. http://dx.doi.org/10.1128/aac.00267-13.

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ABSTRACTLong-acting injectable nanoformulated antiretroviral therapy (nanoART) was developed with the explicit goal of improving medicine compliance and for drug targeting of viral tissue reservoirs. Prior nanoART studies completed in humanized virus-infected mice demonstrated sustained antiretroviral responses. However, the pharmacokinetics (PK) and tissue distribution of nanoART were not characterized. To this end, the PK and tissue distribution of nanoformulated atazanavir (ATV) and ritonavir (RTV) injected subcutaneously or intramuscularly in mice and monkeys were evaluated. Fourteen days

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Golla, Sandeep SV, Pieter J. Klein, Jaco Bakker, et al. "Preclinical evaluation of [(18)F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors." Nucl Med Biol. 42, no. 2 (2014): 205–12. https://doi.org/10.1016/j.nucmedbio.2014.09.006.

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INTRODUCTION: The present study was designed to assess whether [(18)F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([(18)F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET). METHODS: Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input

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Pouzoulet, Frederic, Keyvan Rezai, Zhimin Li, et al. "Preclinical Evaluation of Ibrutinib for Central Nervous System Lymphoma." Blood 128, no. 22 (2016): 4170. http://dx.doi.org/10.1182/blood.v128.22.4170.4170.

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Abstract Introduction Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype. Currently available treatments remain disappointed with a non-optimal complete remission rate and a high relapse rate. As such, novel therapeutic agents are urgently needed. Constitutive activation of the NF-kB pathway via mutations in B cell receptor (BCR) (CD79B) and mutation of MYD 88 and TBL1XR1 pathways plays an important role in PCNSL. Ibrutinib, an inhibitor of BCR signaling, has been found to have significant therapeutic activity in relap

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Tanaka, Chiaki, Terence O’Reilly, John M. Kovarik, et al. "Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data." Journal of Clinical Oncology 26, no. 10 (2008): 1596–602. http://dx.doi.org/10.1200/jco.2007.14.1127.

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PurposeTo use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients.Patients and MethodsInhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship

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Hall, Michael, Zhihong O'Brien, and Sonya Zabludoff. "Abstract C101: Preclinical and clinical pharmacokinetics (PK) of NBF-006, a novel siRNA inhibitor of glutathione-s-transferase P (GSTP) encapsulated in a lipid nanoparticle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC)." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): C101. http://dx.doi.org/10.1158/1535-7163.targ-23-c101.

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Abstract Background: GSTP has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function that regulates multiple key oncogenic pathways such as KRAS and JNK. Since alternative or redundant pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a drug product comprised of GSTP siRNA encapsulated within a novel LNP. It is designed to deliver siRNA to localized and metastatic lung tumors. Unlike other well-established drug modalities, there is a general n

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Freeman, Burgess B., Kaley Blankenship, Michael A. Dyer, and Elizabeth Stewart. "Abstract 4665: Enhancing preclinical testing of agents in patient-derived pediatric solid tumor orthotopic xenografts with pharmacokinetics." Cancer Research 83, no. 7_Supplement (2023): 4665. http://dx.doi.org/10.1158/1538-7445.am2023-4665.

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Abstract Understanding a potential therapeutic agent’s in vivo pharmacokinetics (PK) is important in translating findings from preclinical murine efficacy models to patients. In consideration of this, PK evaluations play a prominent up-front role in our pediatric solid tumor testing pipeline. The aim of such PK studies is to define an agent’s PK under our experimental conditions – i.e. our mouse strain, husbandry, chow, source and lot of agent, and formulation. We ultimately relate our mouse plasma exposures to the known or anticipated exposures in humans or children, thereby deriving a clinic

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Ling, J., R. S. Herbst, D. S. Mendelson, et al. "Apo2L/TRAIL pharmacokinetics in a phase 1a trial in advanced cancer and lymphoma." Journal of Clinical Oncology 24, no. 18_suppl (2006): 3047. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3047.

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3047 Background: Apo2L/TRAIL (Apo2L ligand/tumor necrosis factor-related apoptosis-inducing ligand) is the first recombinant human protein that selectively induces apoptosis or programmed cell death in cancer cells while sparing normal cells. The molecule used in this joint clinical development between Genentech, Inc. and Amgen, Inc., is an optimized recombinant human Apo2L/TRAIL protein produced in E. coli. It displays broad activity in preclinical models of a variety of solid and hematologic cancers. This is the first report of the pharmacokinetics of Apo2L/TRAIL in humans. Methods: Thirty-n

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Almomen, Aliyah, Hadir M. Maher, Nourah Z. Alzoman, Shereen M. Shehata, and Amal Alsubaie. "Flavoured water consumption alters pharmacokinetic parameters and increases exposure of erlotinib and gefitinib in a preclinical study using Wistar rats." PeerJ 8 (September 22, 2020): e9881. http://dx.doi.org/10.7717/peerj.9881.

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Background Erlotinib (ERL) and Gefitinib (GEF) are considered first line therapy for the management of non-small cell lung carcinoma (NSCLC). Like other tyrosine kinase inhibitors (TKIs), ERL and GEF are mainly metabolized by the cytochrome P450 (CYP450) CYP3A4 isoform and are substrates for transporter proteins with marked inter-/intra-individual pharmacokinetic (PK) variability. Therefore, ERL and GEF are candidates for drug-drug and food-drug interactions with a consequent effect on drug exposure and/or drug-related toxicities. In recent years, the consumption of flavoured water (FW) has ga

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Lee, Byeong ill, Min-Ho Park, Seok-Ho Shin, et al. "Quantitative Analysis of Tozadenant Using Liquid Chromatography-Mass Spectrometric Method in Rat Plasma and Its Human Pharmacokinetics Prediction Using Physiologically Based Pharmacokinetic Modeling." Molecules 24, no. 7 (2019): 1295. http://dx.doi.org/10.3390/molecules24071295.

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Tozadenant is one of the selective adenosine A2a receptor antagonists with a potential to be a new Parkinson’s disease (PD) therapeutic drug. In this study, a liquid chromatography-mass spectrometry based bioanalytical method was qualified and applied for the quantitative analysis of tozadenant in rat plasma. A good calibration curve was observed in the range from 1.01 to 2200 ng/mL for tozadenant using a quadratic regression. In vitro and preclinical in vivo pharmacokinetic (PK) properties of tozadenant were studied through the developed bioanalytical methods, and human PK profiles were predi

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Domínguez Moré, Gina Paola, Diana P. Rey, Ivonne H. Valderrama, Luis F. Ospina, and Diana Marcela Aragón. "Rutin and Physalis peruviana Extract: Population Pharmacokinetics in New Zealand Rabbits." Pharmaceutics 16, no. 10 (2024): 1241. http://dx.doi.org/10.3390/pharmaceutics16101241.

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Background/Objectives: An extract of calyces from Physalis peruviana with hypoglycemic activity is being considered as a potential herbal medicine. Preclinical pharmacokinetics (PK) studies of the extract in rats, focusing on plasma concentrations of its main compound, rutin, and its metabolites, revealed PK interactions in the extract matrix that improved the absorption of rutin metabolites compared to the pure compound, among other PK effects. This research aimed to study the PK of rutin alone and in the extract and assess potential PK interactions in the extract matrix on the flavonoid and

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Yao, Xinyue. "Improving brain penetration using elacridara P-glycoprotein and BCRP inhibitor." Theoretical and Natural Science 29, no. 1 (2024): 50–62. http://dx.doi.org/10.54254/2753-8818/29/20240729.

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The central nervous system (CNS) is a site for a myriad of disorders and diseases, such as schizophrenia, Alzheimers disease, and Parkinsons disease. Many medications targeting these illnesses remain challenged due to efflux transporters forming a blood-brain barrier (BBB). To combat such challenges, elacridar shown promise at inhibiting such transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), therefore improving brain penetration. However, as an early clinical candidate, many remain unknown about elacridars pharmacokinetic (PK) properties in the human body

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Liu, J., N. Majd, C. Zou, et al. "OS07.1.A INTEGRATIVE SINGLE NUCLEI, SPATIAL, AND FUNCTIONAL GENOMIC ANALYSES REVEAL DNA-PK DRIVES GLIOBLASTOMA RADIORESISTANCE THROUGH TUMOR CELLS AND THE MYELOID MICROENVIRONMENT." Neuro-Oncology 26, Supplement_5 (2024): v22—v23. http://dx.doi.org/10.1093/neuonc/noae144.065.

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Abstract BACKGROUND Glioblastoma (GBM) is a heterogenous disease comprised of malignant cell states and an immunosuppressive microenvironment that underlie radiotherapy (RT) resistance. Here we integrate genome wide and single cell in vivo functional genomic screens of preclinical models with single nuclei and spatial transcriptomics of human tumors to identify therapeutic vulnerabilities driving GBM radioresistance. MATERIAL AND METHODS Perturb-seq of intracranial GBM models was performed using human (GBM43) or mouse (GL261, SB28) GBM cells expressing CRISPR interference (CRISPRi) machinery,

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Świerczek, Artur, Krzysztof Pociecha, Hanna Plutecka, Marietta Ślusarczyk, Grażyna Chłoń-Rzepa, and Elżbieta Wyska. "Pharmacokinetic/Pharmacodynamic Evaluation of a New Purine-2,6-Dione Derivative in Rodents with Experimental Autoimmune Diseases." Pharmaceutics 14, no. 5 (2022): 1090. http://dx.doi.org/10.3390/pharmaceutics14051090.

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Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34, being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were

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Follman, Kristin, and Marilyn Morris. "Simulation-Based Analysis of the Impact of Renal Impairment on the Pharmacokinetics of Highly Metabolized Compounds." Pharmaceutics 11, no. 3 (2019): 105. http://dx.doi.org/10.3390/pharmaceutics11030105.

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Renal impairment (RI) is a highly prevalent disease which can alter the pharmacokinetics (PK) of xenobiotics, including those that are predominately metabolized. The expression and activity of drug metabolizing enzymes (DMEs) and protein binding of compounds has been demonstrated to be affected in RI. A simulation based approach allows for the characterization of the impact of changes in these factors on the PK of compounds which are highly metabolized and allows for improved prediction of PK in RI. Simulations with physiologically based pharmacokinetic (PBPK) modeling was utilized to define t

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Nutley, B. P., N. F. Smith, A. Hayes, et al. "Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026." British Journal of Cancer 93, no. 9 (2005): 1011–18. http://dx.doi.org/10.1038/sj.bjc.6602823.

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Toyn, Jeremy H., Lorin A. Thompson, Kimberley A. Lentz та ін. "Identification and Preclinical Pharmacology of theγ-Secretase Modulator BMS-869780". International Journal of Alzheimer's Disease 2014 (2014): 1–22. http://dx.doi.org/10.1155/2014/431858.

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Alzheimer’s disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-βpeptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased byγ-secretase modulators (GSM), which are small molecules that modulateγ-secretase, an enzyme essential for Aβproduction. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβpeptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing byγ-secretase and lowered brain Aβ1-42 with

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Choi, Suein, Seunghoon Han, Sangil Jeon, and Dong-Seok Yim. "Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)." Pharmaceutics 11, no. 7 (2019): 336. http://dx.doi.org/10.3390/pharmaceutics11070336.

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CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were develo

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Choi, Young Hee, and Young-Won Chin. "Multifaceted Factors Causing Conflicting Outcomes in Herb-Drug Interactions." Pharmaceutics 13, no. 1 (2020): 43. http://dx.doi.org/10.3390/pharmaceutics13010043.

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Metabolic enzyme and/or transporter-mediated pharmacokinetic (PK) changes in a drug caused by concomitant herbal products have been a primary issue of herb and drug interactions (HDIs), because PK changes of a drug may result in the alternation of efficacy and toxicity. Studies on HDIs have been carried out by predictive in vitro and in vivo preclinical studies, and clinical trials. Nevertheless, the discrepancies between predictive data and the clinical significance on HDIs still exist, and different reports of HDIs add to rather than clarify the confusion regarding the use of herbal products

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Niloy, Kumar Kulldeep, Jamie Horn, Nazmul H. Bhuiyan, et al. "Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog." Pharmaceutics 17, no. 6 (2025): 765. https://doi.org/10.3390/pharmaceutics17060765.

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Background: Mithramycin (MTM) is a polyketide anti-cancer natural product previously identified as an EWS-FLI1 inhibitor. This oncogenic transcription factor is a canonical target for drug development in Ewing sarcoma. However, poor pharmacokinetics have been identified as a critical liability of MTM, preventing its further development. Through semisynthetic chemical modifications, we identified mithramycin SA-Trp (MTMSA-Trp) as being a pharmacologically superior congener. To explore their pharmacokinetic (PK) differences, this study examined the plasma PKs and plasma protein binding (PPB) of

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Gonzalez Hernandez, Ferran, Simon J. Carter, Juha Iso-Sipilä, et al. "An automated approach to identify scientific publications reporting pharmacokinetic parameters." Wellcome Open Research 6 (April 21, 2021): 88. http://dx.doi.org/10.12688/wellcomeopenres.16718.1.

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Pharmacokinetic (PK) predictions of new chemical entities are aided by prior knowledge from other compounds. The development of robust algorithms that improve preclinical and clinical phases of drug development remains constrained by the need to search, curate and standardise PK information across the constantly-growing scientific literature. The lack of centralised, up-to-date and comprehensive repositories of PK data represents a significant limitation in the drug development pipeline.In this work, we propose a machine learning approach to automatically identify and characterise scientific p

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Chauhan, Dharminder, Guilan Li, Klaus Podar, et al. "Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells." Blood 104, no. 8 (2004): 2458–66. http://dx.doi.org/10.1182/blood-2004-02-0547.

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Abstract Bortezomib (PS-341), a selective inhibitor of proteasomes, induces apoptosis in multiple myeloma (MM) cells; however, prolonged drug exposure may result in cumulative toxicity and the development of chemoresistance. Here we show that combining PK-11195 (PK), an antagonist to mitochondrial peripheral benzodiazepine receptors (PBRs), with bortezomib triggers synergistic anti-MM activity even in doxorubicin-, melphalan-, thalidomide-, dexamethasone-, and bortezomib-resistant MM cells. No significant cytotoxicity was noted in normal lymphocytes. Low-dose combined PK and bortezomib treatme

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Jang, Mingui, Minsung Kang, Eunseok Lee, and Dongseong Shin. "Ocular and Plasma Pharmacokinetics of Enavogliflozin Ophthalmic Solution in Preclinical Species." Pharmaceuticals 17, no. 1 (2024): 111. http://dx.doi.org/10.3390/ph17010111.

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An enavogliflozin ophthalmic solution (DWRX2008) is being developed to treat diabetic retinopathy and macular edema. This study evaluated the ocular distribution and plasma pharmacokinetics (PKs) of enavogliflozin in animal species. A sample of [14C] enavogliflozin was ocularly administered to two rabbits per time point at single doses of 600 μg/eye to evaluate ocular PK, which was evaluated using autoradiography until 48 h post-dose. Plasma concentrations after ocular administration in six rabbits, three rats, and three beagle dogs with single doses of 400 μg, 25 μg, and 100 μg, respectively,

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Li, Tommy, Ida H. Hiemstra, Christopher Chiu, et al. "Novel Semi-Mechanistic Model Leveraging Preclinical and Clinical Data to Inform the Recommended Phase 2 Dose (RP2D) Selection for Epcoritamab (DuoBody CD3xCD20)." Blood 136, Supplement 1 (2020): 35–36. http://dx.doi.org/10.1182/blood-2020-139457.

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Introduction: Epcoritamab (DuoBody-CD3×CD20) is a subcutaneously administered bispecific antibody (bsAb) that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, resulting in T-cell activation and expansion and selective T-cell-mediated killing of CD20+ cells. Target engagement (TE) and crosslinking of CD3 and CD20 (trimer formation) lead to activation and expansion of T cells, which in turn leads to tumor cell killing and is the first step driving the pharmacology of epcoritamab. Hence, the optimal clinical dose of epcoritamab can be informed by TE and trimer formation. Unli

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Kinsale, Talisa S., Mackenzie L. Cottrell, Linying Li, et al. "Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP." Pharmaceutics 16, no. 2 (2024): 201. http://dx.doi.org/10.3390/pharmaceutics16020201.

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Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ran

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Santich, Brian H., Charlotte A. Russell, LinLin Wang, et al. "Abstract 566: Preclinical and translational pharmacokinetic (PK) modeling of the self-assembling and disassembling (SADA) bispecific fusion protein CD38-SADA for first-in-human (FIH) pretargeted radioimmunotherapy (PRIT)." Cancer Research 85, no. 8_Supplement_1 (2025): 566. https://doi.org/10.1158/1538-7445.am2025-566.

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Abstract Background: PRIT is designed to deliver tumor-targeted radiation while limiting exposure to healthy tissues. CD38-SADA binds CD38 and select radioisotopes chelated to tetraxetan (DOTA) and contains a p53-derived domain mediating the self-assembly of tetramers from monomers in a reversible, concentration-dependent manner. Preclinical studies have demonstrated dose-dependent anti-tumor efficacy of two-step CD38-SADA PRIT with 177Lu-DOTA administered 48h after an initial CD38-SADA infusion. Here, we report preclinical PK models and human simulations that informed the FIH study design and

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Buchner, Anton, Udo W. Mueller, Peter Bias, and Andreas Engert. "Preclinical and clinical data for tbo-filgrastim: A short-acting filgrastim." Journal of Clinical Oncology 31, no. 15_suppl (2013): e13555-e13555. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13555.

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e13555 Background: Tbo-filgrastim is a G-CSF approved in the US as a biologic under the BLA 351(a) pathway, for reducing duration of severe neutropenia (DSN) in patients with non-myeloid malignancies receiving chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia (FN). Here, we summarize data from the development program (16 preclinical studies; 2 Phase I and 3 Phase III clinical studies). Methods: Preclinical: The PK, safety pharmacology, PD, and toxicology of tbo-filgrastim vs reference filgrastim were investigated in 3 in vitro studies and 13 animal mo

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Yang, Sung-yoon, Lien Thi Ngo, Soyoung Lee, et al. "Model-Based Evaluation of HangAmDan-B1 and Afatinib Combination Therapy in HCC827 Xenograft Mice with Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor." Pharmaceuticals 18, no. 5 (2025): 748. https://doi.org/10.3390/ph18050748.

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Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to quantitatively examine the exposure–response relationship and synergistic interactions through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: A PK/PD model was established and validated based on tumor growth profiles from a xenograft mouse study of gefitinib-resistant

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Yao, Yunqi, Xiaoning Yang, Jing Li, et al. "Preclinical Characterization of Efficacy and Pharmacodynamic Properties of Finotonlimab, a Humanized Anti-PD-1 Monoclonal Antibody." Pharmaceuticals 18, no. 3 (2025): 395. https://doi.org/10.3390/ph18030395.

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Background/Objectives: Finotonlimab (SCTI10A) is a humanized anti-PD-1 antibody tested in Phase III trials for several solid tumor types. Methods: This study characterized the in vitro and in vivo efficacy, Fc-mediated effector function, and non-clinical PK/PD properties of finotonlimab. Results: The results demonstrated that finotonlimab is effective in stimulating human T cell function in vitro and exhibits marked antitumor efficacy in vivo using both PD-1-humanized and PBMC-reconstructed mouse models. Additionally, finotonlimab exhibited minimal impact on the activation of effector cells vi

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Le Moigne, Ronan, Paul Pearson, Veronique Lauriault, et al. "Preclinical and clinical pharmacology of EPI-7386, an androgen receptor N-terminal domain inhibitor for castration-resistant prostate cancer." Journal of Clinical Oncology 39, no. 6_suppl (2021): 119. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.119.

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119 Background: EPI-7386 is the newest of the “anitens”, a new class of compounds designed to inhibit androgen receptor activity by binding to the N-terminal domain (NTD) of the AR. Through this novel method of AR inhibition, anitens can block AR transcription even in the presence of AR ligand-binding domain (LBD) resistance mechanisms including point mutations and splice variants. Compared to the first generation aniten, EPI-506, which showed poor pharmacokinetic properties in patients, EPI-7386 is metabolically stable in vitro and in vivo. A Phase 1 clinical trial of EPI-7386 in metastatic c

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