The Journal of Clinical Pharmacology最新文献

{"title":"Has Pharmacologic Contextualization Become a Lost Art? How Can We Revive the Integrator Pharmacologist?","authors":"Rajesh Krishna PhD","doi":"10.1002/jcph.70141","DOIUrl":"10.1002/jcph.70141","url":null,"abstract":"<p>Pharmacologic contextualization—the disciplined practice of situating clinical pharmacokinetic (PK) findings within a mechanistic framework of pharmacodynamics (PD), receptor biology, and translational preclinical insights—appears increasingly absent in the contemporary biomedical literature. Many recent publications reporting the human pharmacokinetics of a novel molecule illustrates this erosion: while the authors meticulously describe plasma concentration–time profiles, they fail to provide meaningful integration with the underlying pharmacologic rationale that should contextualize such data.</p><p>The reported study presents exposure metrics (e.g., peak maximum concentrations, area under the curve, and trough concentrations) as static descriptors, without linking them to nonclinical or mechanistic data that might explain their pharmacologic relevance. Historically, PK parameters were not endpoints in themselves but vehicles to bridge dose, exposure, and biological effect. The failure to anchor these results to receptor occupancy, enzyme modulation, or biomarker response represents a rupture in translational continuity. This neglect obscures how the achieved concentrations inform the therapeutic window or elucidate the drug's dose–response dynamics.</p><p>Pharmacologic contextualization depends on a mechanistic mindset, one that interprets PK findings through the lens of target affinity, binding kinetics, and system biology. When studies omit receptor dynamics or occupancy relationships, they surrender the interpretive power that distinguishes pharmacology from mere bioanalytics. Without context, plasma levels become uninterpretable abstractions, and the essential question—<i>what exposure matters, and why?</i>—remains unanswered.</p><p>The apparent loss of pharmacologic contextualization reflects deeper systemic shifts in drug development culture. Increasing specialization has fragmented the discipline: pharmacometricians focus on model fidelity, clinicians on safety endpoints, and molecular biologists on mechanistic minutiae. The integrative “clinical” pharmacologist—once the bridge between these domains—has become rare. As a result, publications often privilege quantitative precision over conceptual coherence. The art lies not in calculating a half-life to three decimal places, but in explaining what that half-life <i>means</i> for receptor engagement and downstream biology.</p><p>Contemporary clinical pharmacology is also constrained by regulatory pragmatism. Studies are designed to satisfy International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and regulatory health authority expectations for first-in-human characterization, often stripped of the exploratory pharmacologic inquiries that once illuminated dose rationale. The emphasis on “meeting requirements” disincentivizes mechanistic curiosity. Consequently, even when rich preclinical PD or biomarker data exist, they are seldom woven i","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70141","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145641765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Enhancement of Radionuclide Therapy Using Radiopharmaceutical–Drug Combinations in Oncology","authors":"Erik T. te Beek MD, PhD,&nbsp;Sophie L. Gerritse MD,&nbsp;Frederik A. Verburg MD, PhD","doi":"10.1002/jcph.70128","DOIUrl":"10.1002/jcph.70128","url":null,"abstract":"<p>Despite the ability of radionuclide therapy to significantly prolong progression-free survival and overall survival in several different cancer types, most patients show only partial tumor responses or stable disease, while some patients show progressive disease in spite of therapy. Co-administration or sequential administration of selected drugs whose mechanism of action complement the properties of radionuclide therapy may provide a pharmacological basis to potentially overcome some of the limitations of radiopharmaceutical therapy and may enhance clinical efficacy by additive or synergistic cytotoxic effects. The rational design and evaluation of novel radiopharmaceutical–drug combinations and optimization of dosage and administration schedules, within the complex context of individualized multimodal cancer treatment, requires a multidisciplinary approach, principally including clinical pharmacology. Potential strategies include upregulation of target receptors, co-administration of cytotoxic chemotherapeutic drugs, co-administration of drugs that inhibit DNA damage repair, co-administration of drugs that inhibit the mammalian (or mechanistic) target of rapamycin signaling pathway, co-administration of drugs that activate immune responses, and co-administration aimed at modifying pharmacokinetics to prolong retention time of radiopharmaceuticals and increase the absorbed radiation dose. Several phase II trials are currently underway, highlighting a role for clinical pharmacology in the exploration of methods to further improve efficacy of radionuclide therapy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"US FDA's Strategic Transition of Animal to Non-Animal Alternatives for Monoclonal Antibody Development: A Much Needed Fuel to Incentivize Innovation","authors":"Rajesh Krishna PhD","doi":"10.1002/jcph.70127","DOIUrl":"10.1002/jcph.70127","url":null,"abstract":"&lt;p&gt;After years of investigating, on April 10, 2025, the US Food and Drug Administration (FDA) finally announced a major shift in its regulatory approach: the agency will begin to reduce, refine, or potentially replace animal testing requirements in the development of monoclonal antibody (mAb) therapies and other drugs with alternative, human-relevant methods, collectively referred to as New Approach Methodologies (NAMs). The exact time by which such a transition will occur has not yet been shared. These NAMs encompass mechanistic and computational modeling, cell-based assays, and advanced systems like organoids and organ-on-a-chip (OoC) platforms.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The goal is to make drug evaluation more ethical, predictive, and efficient, and these changes when implemented at scale will be globally transformative.&lt;/p&gt;&lt;p&gt;While this initiative on face value marks a steadfast move toward ending the long-standing reliance on animal testing, the deeper argument is a long overdue step in ensuring risk is better estimated in the context of human-specific responses. The FDA seeks to establish leadership in regulatory science with human-centric models. Animal models often fail to accurately reflect human biology. Human-derived systems, bioengineered models such as organoids and OoC technology, can identify human-specific toxicities or responses that traditional models may miss. This move conforms with previous congressional reforms, most notably the FDA Modernization Act 2.0, which legally enabled non-animal testing approaches. A proposed Modernization Act 3.0 aims to solidify implementation and will lend legislative support when passed (https://www.congress.gov/bill/119th-congress/senate-bill/355).&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The FDA will also consider real-world safety data from regions where a drug has already been studied in humans, reducing the necessity for local animal studies. Again, the exact contextual details of such circumstances are evolving.&lt;/p&gt;&lt;p&gt;Effective right away, inclusion of NAMs data in Investigational New Drug (IND) applications is encouraged, potentially enabling circumventing animal data where robust human-relevant evidence exists. It is important to make note that the agency is not suggesting eliminating risk assessment from animal studies, rather they want to pivot toward more meaningful models of assessing human risk. A pilot program will be launched within a year, targeting selected mAb developers to test NAM-driven strategies under FDA consultation. These trials will quite significantly inform future policy shifts. The FDA will also host public workshops to gather stakeholder input and refine implementation based on scientific and industry feedback.&lt;/p&gt;&lt;p&gt;It is expected that the FDA will revise guidelines to include NAMs in data submission frameworks and offer accelerated review pathways for mAb programs that demonstrate sound non-animal evidence. Significant interagency validation will also be necessary. It is pl","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1 Study to Assess the Effect of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Dordaviprone","authors":"Shamia L. Faison PhD,&nbsp;Joelle Batonga MSc,&nbsp;Thangam Arumugham PhD,&nbsp;Angela Bartkus BSN RN,&nbsp;Marion E. Morrison MD,&nbsp;Mark J. Mullin BS,&nbsp;Timothy Tippin PhD,&nbsp;Odin Naderer PharmD","doi":"10.1002/jcph.70129","DOIUrl":"10.1002/jcph.70129","url":null,"abstract":"<p>Dordaviprone (ONC201) is a small molecule protease activator being developed for gliomas. The aim of this work was to evaluate the pharmacokinetics and safety of dordaviprone when administered to participants with moderate hepatic impairment compared to healthy matched participants. A non-randomized, open-label, single-dose study was conducted in eight participants with moderate hepatic impairment classified according to Child–Pugh criteria, and eight healthy participants matched based on age (<span>+</span>10 years), body mass index (BMI; <span>+</span>20%), and sex. Plasma concentrations of dordaviprone and the major inactive metabolite, ONC207, were determined by a validated liquid chromatography–tandem mass spectrometry method. Exposure following oral administration of 125 mg dordaviprone was increased in participants with moderate hepatic impairment relative to healthy matched participants, with the largest impact occurring on AUC. Ratios of geometric means and 90% confidence intervals (CIs) of dordaviprone exposure for C_max, AUC_last, and AUC_inf in the moderate hepatic impairment cohort compared to the healthy matched cohort were 1.21 (0.88, 1.67), 1.50 (1.02, 2.20), and 1.55 (1.05, 2.29), respectively. Treatment-emergent adverse events were mild in nature and considered not related to dordaviprone administration. While administration of dordaviprone in participants with moderate hepatic impairment led to increased dordaviprone exposures, the anticipated increase after the recommended 625 mg dose is within exposures assessed in the thorough QT study. Therefore, no dose adjustment in patients with mild or moderate hepatic impairment is recommended.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on “Population Pharmacokinetics of Valemetostat and Exposure–Response Analyses of Efficacy and Safety in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma”","authors":"Manish R. Bhise M.Pharm, PhD,&nbsp;Ajay Kumar M.Pharm, PhD,&nbsp;Diksha Cheeda M.Pharm","doi":"10.1002/jcph.70133","DOIUrl":"10.1002/jcph.70133","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We read with great interest the study by Hiroyuki et al&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; examining the population pharmacokinetics and exposure–response relationships of valemetostat in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL). The integration of data across multiple trials and the focus on unbound drug exposure provide an important step toward dose justification for this rare and aggressive lymphoma subtype.&lt;/p&gt;&lt;p&gt;Although the pharmacokinetic model was robust, several aspects of the exposure–response (ER) analyses raised concerns regarding its translation into clinical decision-making. The efficacy analysis concluded a flat relationship between unbound concentration and overall response rate; however, this inference stems from a single-dose dataset with narrow exposure variability. Without multiple dose levels, the ER slope is statistically underpowered to detect a clinically relevant gradient. In practice, oncologists may incorrectly interpret the absence of a modeled relationship as evidence that exposure is irrelevant to efficacy, potentially overlooking the need for therapeutic drug monitoring in patients with altered metabolism or those taking multiple medications.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;For safety endpoints, positive exposure–toxicity relationships were observed for anemia and thrombocytopenia; however, simulated differences between 100 and 200 mg daily doses were reported as ≤6%. Such conclusions are sensitive to modeling assumptions because dose reductions and interruptions were common in the underlying trials. By using the concentration up to the event (Cavg, TE) as the primary exposure metric, the model risks incorporating dose modification decisions often triggered by toxicity into the exposure variable itself. This circularity can obscure causality, and in clinical practice, it may lead to an underestimation of risk at standard dosing, potentially delaying necessary interventions, such as early transfusion support or dose adjustment in vulnerable patients.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The handling of covariates also requires caution. Although alpha-1-acid glycoprotein influences total exposure without affecting unbound concentrations, the model did not fully explore how comorbid hepatic dysfunction and high baseline lactate dehydrogenase interact with exposure to shape toxicity risk. In the clinical setting, these are precisely the subgroups of frail patients with hepatic impairment and high tumor burden, where safety margins matter most. In the absence of stratified validation, clinicians could be left with an overly general reassurance of safety at 200 mg, when in fact, targeted dose adjustments may be justified in high-risk subgroups.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Finally, the simulations suggested comparable safety profiles between 100 and 200 mg, but the lack of external validation in independent datasets leaves uncertainty about generalizability. In real-world practice, such u","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70133","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145524608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Pharmacology Insights for Small Molecule and Antibody-Based Drug Products Approved for Multiple Immune-Mediated Indications","authors":"Yan Xu MD, PhD,&nbsp;Bharath Kumar Kandadi Muralidharan MS,&nbsp;Konstantine Skordos PhD","doi":"10.1002/jcph.70121","DOIUrl":"10.1002/jcph.70121","url":null,"abstract":"<p>Developing therapeutics for multiple immune-mediated indications has become a prominent strategy, driven by advances in disease biology, pharmacology, clinical and regulatory science. We analyzed 34 FDA-approved small molecular and antibody-based drug products with more than one adult immune-mediated inflamamatory indication by December 2024. A clear trend toward pathway-driven development was seen, with shared targets (e.g., TNFα, IL-17, IL-23, and JAKs) enabling indication expansion. Approved indications per product ranged from 2 to 8 (median: 3). Over time, the median gap between subsequent indication approvals decreased from 3.2 years (range 1.1–12.8) for products first approved in 1998–2008 to 1.7 years (range 0.67–2.75) for those approved after 2018, reflecting improved efficiency likely due to broader adoption of pathway-based strategies. Route of administration also evolved for antibody-based therapies, with median delays of 5.8–6.0 years for intravenous-to-subcutaneous (IV-to-SC) and 4.4–8.5 years for subcutaneous-to-intravenous (SC-to-IV) transitions. Fewer than 25% of therapies kept the same dosing regimen across indications, with small molecules more likely to retain dosing (62.5%, 5/8) than antibodies (11.5%, 3/26), indicating the need for tailored approaches based on disease context, tissue involvement, and patient characteristics. Key clinical pharmacology considerations include rational dose selection, surrogate and extrapolation strategies, and model-informed bridging, leveraging existing data to inform subsequent indications. Early regulatory engagement, strategic target selection, robust trial design, harmonized safety database, and cross-functional coordination are critical. Our analysis provides insights to guide multi-indication development to improve patient access to therapies for diverse immune-mediated disorders.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Oral Contraceptive Drug–Drug Interaction Study With Ganfeborole, a New Anti-Tuberculosis Agent","authors":"Laura Iavarone MSc, PharmD,&nbsp;Silvia M. Lavezzi PhD,&nbsp;Antonio J. Carcas MD,&nbsp;Tetyana Chaychenko MD,&nbsp;Raquel Gabarro-Carrion PhD,&nbsp;Arturo Gómez López de las Huertas MD,&nbsp;Stephanie Gresham MSc,&nbsp;Alicia Marín-Candón MD,&nbsp;Sophie L. Penman PhD,&nbsp;Katie Rolfe MS,&nbsp;Simon Tiberi MD,&nbsp;David Barros-Aguirre PhD,&nbsp;Alberto M. Borobia MD,&nbsp;the ERA4TB consortium","doi":"10.1002/jcph.70161","DOIUrl":"10.1002/jcph.70161","url":null,"abstract":"<p>New drugs are urgently needed to treat drug-resistant tuberculosis in combination regimens. Ganfeborole demonstrated bactericidal activity and good tolerability in clinical trials. In preclinical studies, ganfeborole showed embryofetal developmental effects, currently mandating highly effective non-user dependent contraception in women of childbearing potential. We conducted a Phase 1, open-label, single-center, fixed sequence, 1-way drug–drug interaction (DDI) study in 20 healthy women of non-childbearing potential aged 18-65 years. The primary objective was to assess ganfeborole's effect at steady-state (20 mg daily) on single dose pharmacokinetics of ethinyl estradiol [EE] 0.03 mg/levonorgestrel [LNG] 15 mg (Bayer). Endpoints were EE and LNG area under the plasma concentration-time curve extrapolated to infinity (AUC_(0-inf)) and maximum concentration (<i>C</i>_max). Unexpected fluctuations in individual EE and LNG plasma concentration-time profiles limited the number of acceptable endpoints for the analysis. Geometric mean ratios (GMR; EE/LNG+ganfeborole versus EE/LNG alone) and respective 90% confidence intervals (CI) for EE <i>C</i>_max (0.96, 0.85-1.09), LNG AUC_(0-inf) (1.10, 0.98-1.23) and LNG <i>C</i>_max (1.08, 0.97-1.19) met criteria for lack of DDI (90% CI 0.80-1.25). However, the GMR for EE AUC_(0-inf) was 0.88, with 90% CI 0.55-1.41. While post-hoc analyses on partial AUCs (up to 8 and 24 h) provided GMR 90% CIs within 0.80-1.25, a lack of DDI could not be concluded. No treatment-related adverse events were reported. Further assessments of potential DDI between ganfeborole and combined oral contraceptives are warranted. Future trials will maintain strict contraception requirements.</p><p>Clinical Trial Registration: NCT06354257 (registration date: 2024-04-03); EudraCT: 2023-507839-38-00</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12966810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep-Learning- versus Hypothesis-Driven Modeling in Model-Informed Drug Development: A PK/PD Case Study","authors":"Roberto Gomeni PhD FCP,&nbsp;Françoise Bressolle-Gomeni PhD","doi":"10.1002/jcph.70174","DOIUrl":"10.1002/jcph.70174","url":null,"abstract":"<p>Model-informed drug development (MIDD) has traditionally been guided by hypothesis-driven modeling, in which models are constructed based on established biological mechanisms, physicochemical principles, and experimental hypotheses. More recently, the rise of artificial intelligence has enabled data-driven modeling approaches that often bypass explicit mechanistic assumptions. The potential synergy between these two paradigms is reshaping strategies for implementing MIDD. This study aims to compare deep-learning-driven and hypothesis-driven approaches, highlighting their respective strengths, limitations, and opportunities for integration. A case study is presented with the re-analysis of warfarin PK and PK/PD using both modeling paradigms. The comparative PK analysis indicated that the deep-learning model achieved predictive performance comparable to, and numerically slightly better than, hypothesis-driven modeling based on a one-compartment PK model. The hypothesis-based PK/PD analysis was conducted using three model structures: direct effect, effect compartment, and indirect response. The results of these analyses, including the estimated clinical dose, were compared with those obtained from the deep-learning approach. The deep-learning model demonstrated predictive performance similar to that of the effect compartment and indirect response models and yielded a comparable estimate of the effective dose across the two modeling approaches. A simulation-based sensitivity analysis was conducted to evaluate the robustness of the dose selection derived from the deep-learning-based modeling approach. The outcomes of the analysis suggest that effective implementation of the MIDD paradigm may be enhanced through the complementary use of deep-learning-based approaches alongside established hypothesis-driven, mechanistic models, thereby supporting evidence-based drug development and regulatory decision-making.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12965040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147367067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic Modeling Practice of Time-Varying Clearance: Insights from a First-in-Human Study Case","authors":"Yongjun Hu PhD,&nbsp;Lan Gao PhD,&nbsp;Ronald Kong PhD","doi":"10.1002/jcph.70171","DOIUrl":"10.1002/jcph.70171","url":null,"abstract":"<p>Accurate characterization of time-varying clearance (CL) is critical during early drug development, as it informs clinical study design and dosing strategies for future trials. However, detecting and modeling time-varying clearance is challenging due to limited data availability in early clinical development. Using pharmacokinetic data from a well-controlled first-in-human (FIH) study with single and multiple ascending doses, this study explored time-varying clearance, dose proportionality, and meal effects on pharmacokinetics (PK) of utreloxastat. Initial data analysis revealed time-varying systemic clearance, more-than-dose-proportional kinetics, and meal-dependent PK alterations, which informed the development of a population pharmacokinetic (PopPK) model. A systematic evaluation of twelve distinct time-varying clearance models identified an exponential time-varying clearance model within a two-compartment framework, incorporating first-order absorption with eight transit compartments, as the best fit to the data. Covariate analysis confirmed that sex, age, and body weight were not significant predictors of variability. This study is the first to showcase a comparative evaluation of time-varying clearance for a small molecule. It highlights the innovative application of time-varying clearance modeling during the FIH study as a pivotal step in optimizing model-informed dosing strategies. This approach underscores its importance in addressing non-linear pharmacokinetics and enhancing drug development practices for future clinical trials.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12955343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147345555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetics Analysis of Talazoparib and Enzalutamide Combination Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer","authors":"Mark Hadigol PhD,&nbsp;Jason H. Williams PhD,&nbsp;Haihong Shi MSc/MBA,&nbsp;Derek Z. Yang PharmD,&nbsp;Justin Hoffman PharmD,&nbsp;Diane D. Wang PhD","doi":"10.1002/jcph.70125","DOIUrl":"10.1002/jcph.70125","url":null,"abstract":"<p>The poly(ADP-ribose) polymerase inhibitor talazoparib, combined with the androgen receptor inhibitor enzalutamide is approved for patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) in the US and with mCRPC in whom chemotherapy is not clinically indicated in Europe. We provide a population pharmacokinetic model for this combination in patients with mCRPC unselected for HRR deficiencies from TALAPRO-2 (NCT03395197). The pooled dataset included 811 patients treated with enzalutamide plus either talazoparib or placebo. The final enzalutamide model was a two-compartment model with first-order absorption and inter-individual variability (IIV) on apparent clearance (CL_e/F_e) and apparent central volume of distribution (Vc_e/F_e) and included effects of baseline body weight and age on CL_e/F_e and Vc_e/F_e. For the active metabolite N-desmethyl enzalutamide, a two-compartment model with IIV on CL_n and Vc_n adequately described the observed data and included the effect of body weight on CL_n and Vc_n. The final talazoparib model was well characterized by a two-compartment model with first-order absorption and IIV on talazoparib apparent base clearance (CL_t0/F_t) and Vc_t/F_t. The effect of enzalutamide and N-desmethyl enzalutamide on CL_t/F_t of talazoparib was modeled through a linear relationship. The single covariate effect of baseline creatinine clearance on CL_t0/F_t showed that relative to the reference value for normal renal function, CL_t0/F_t decreased by 8% for mild, 27% for moderate, and 46.7% for severe renal impairment. Simulations showed that a dose reduction of enzalutamide does not require talazoparib dose modification since the magnitude of exposure reduction for talazoparib was not considered clinically significant.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"66 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12934543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}