The Journal of Clinical Pharmacology最新文献

{"title":"Optimizing Zanubrutinib Dosing in Patients: A PBPK-BO Model Approach to Drug–Drug Interactions and Patients with Hepatic Impairment","authors":"Jiawei Ren BS,&nbsp;Dan Shan MS,&nbsp;Guijuan Yue PhD,&nbsp;Qiang He MS","doi":"10.1002/jcph.70042","DOIUrl":"10.1002/jcph.70042","url":null,"abstract":"<p>This study aimed to develop a physiologically based pharmacokinetic and Bruton's tyrosine kinase (BTK) occupancy (PBPK-BO) model to evaluate the pharmacokinetics (PK) and BTK occupancy (BO) of zanubrutinib (ZAN), particularly in relation to drug–drug interactions (DDIs) involving cytochrome P450 3A4 (CYP3A4) modulators and for patients with hepatic impairment. Population PBPK-BO and DDI models for ZAN were constructed using physicochemical properties, pharmacokinetic data, BTK occupancy levels, and physiological parameters. The PBPK-BO model was validated against clinically measured PK, DDI, and BO data, demonstrating accurate predictions of ZAN's plasma concentration and the time–course profiles of BO. The predicted ratios of AUC and C_max in patients consistently fell within the acceptable range of 1.5-fold. The predicted fold-change ratios in DDIs and in patients with hepatic impairment also are in good agreement with the observed data. These findings confirm the reliability of the PBPK-BO model for predicting PK and BO of ZAN. Based on the model with &gt;95% BO as a clinical efficacy threshold, the recommended dosing of ZAN should be reduced to 40 mg once daily (OD) when used with strong CYP3A4 inhibitors such as itraconazole or clarithromycin. For moderate CYP3A4 inhibitors like fluconazole, dosing should be adjusted to either 160 mg OD or 80 mg twice daily (BID). Additionally, the model advises against concomitant administration of ZAN with strong CYP3A4 inducers such as rifampicin or moderate inducers like rifabutin. Furthermore, the PBPK-BO model suggests that dosing regimens should be reduced to 80 mg BID or 160 mg OD in patients with severe hepatic impairment. The PBPK-BO model provides a robust framework for clinical decision-making, aimed at optimizing treatment outcomes in patients receiving ZAN therapy.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1286-1296"},"PeriodicalIF":0.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036053","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":"First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral Complement Factor D Inhibitor BCX9930 in Healthy Participants","authors":"Matthew Davidson PharmD,&nbsp;Xilin Chen PhD,&nbsp;Amanda Mathis PhD,&nbsp;Sylvia Dobo MD,&nbsp;Melanie Cornpropst PharmD, PhD,&nbsp;Fugang Zhu PhD,&nbsp;Cynthia Parker BS,&nbsp;David Reynolds PhD,&nbsp;Yarlagadda S. Babu PhD,&nbsp;Stuart Mair MBChB, DRCOG, DCPSA, FFPM,&nbsp;William P. Sheridan MB, BS","doi":"10.1002/jcph.70032","DOIUrl":"10.1002/jcph.70032","url":null,"abstract":"<p>BCX9930 is a potent, selective oral inhibitor of complement Factor D that inhibits the activation of the complement alternative pathway (AP) and has the potential for treatment of complement-mediated diseases. This was a first-in-human, randomized, double-blind, placebo-controlled study that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BCX9930 in healthy participants. Safety and tolerability were evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 were measured using validated liquid chromatography-dual mass spectrometry; PD effects were assessed via multiple assays. Participants were enrolled into seven single dose cohorts (10-2000 mg) and eight multiple-dose cohorts (50-500 mg every 12 h [Q12h] and 1000-2000 mg every 24 h [Q24h]). Enrollment comprised 152 participants (122 received BCX9930 and 30 received placebo). Following BCX9930 administration, plasma exposure was approximately dose proportional across all doses. The effective half-life (t_1/2) ranged from 6.45 to 7.75 h for Q12h doses at steady state. Clearance and times to maximum concentration (T_max) were similar across all doses studied, without evidence of dose- or time-dependent clearance. BCX9930 administration resulted in rapid, potent, and dose-dependent AP inhibition. Doses ≥200 mg Q12h and ≥1000 mg Q24h achieved maximal suppression (&gt;98% relative to baseline levels) of AP activity over the full dosing interval. No clinically significant dose-related trends in adverse events (AEs), laboratory values, vital signs, or electrocardiograms were noted. BCX9930 was safe and generally well tolerated in this first-in-human study and displayed highly favorable PK and PD profiles. These results support Factor D inhibition as a promising strategy for treatment of complement-mediated diseases.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1116-1126"},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020526","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":"Expansion of a Pharmacokinetic Model for Diazepam to Characterize Real-World IV and Oral Data in Children With and Without Obesity","authors":"Sean M. McCann BS,&nbsp;Jiali Wen PharmD,&nbsp;Stephen J. Balevic MD, PhD,&nbsp;William J. Muller MD, PhD,&nbsp;Amira Al-Uzri MD,&nbsp;Chi D. Hornik PharmD,&nbsp;Marisa L. Meyer DO,&nbsp;Sarah G. Anderson MS,&nbsp;Elizabeth H. Payne PhD,&nbsp;Sitora Turdalieva MS,&nbsp;James M. Chamberlain MD,&nbsp;Daniel Gonzalez PharmD, PhD,&nbsp;the Best Pharmaceuticals for Children Act Pediatric Trials Network Steering Committee","doi":"10.1002/jcph.70027","DOIUrl":"10.1002/jcph.70027","url":null,"abstract":"<p>Diazepam is a benzodiazepine approved for use in adults and children. The label incorporates recommended dosing for status epilepticus in children. Published population pharmacokinetic (PK) modeling recommends an intravenous bolus dose of 0.2 mg/kg capped at 8 mg to reach the suggested target exposure of 200-600 ng/mL at 10 min post dose in children up to 17 years of age. This model was developed for children generally without obesity based on IV data, and it is unclear how increased body weight may affect exposure or target attainment given capped dosing. Diazepam concentrations after IV or oral administration for 61 children aged 2.5 to 20.6 years were used to externally evaluate the model including the addition of fixed oral absorption parameters. Then, PK parameters were re-estimated with the external population alone and again in combination with the original population. Re-estimated parameters from the combined population were used to simulate recommended dosing for children with and without obesity. The external dataset included 88 plasma concentrations from 61 children (54 with obesity) receiving diazepam per standard of care. The external evaluation resulted in 34.5% of predicted values within 30% of the observed concentration. Parameter re-estimation resulted in increased central volume of distribution (26% increase from a previous model), reduced peripheral volume of distribution and intercompartmental clearance, and similar clearance estimates. Simulations demonstrated that dosing caps may prevent children with obesity from reaching the suggested target exposure that is recommended for the treatment of status epilepticus. Further study is needed to evaluate the target exposure range in this population.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1135-1149"},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988924","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":"How to Peer Review a Systematic Review: A Peer-Reviewer's Guide to Reviewing Reviews","authors":"Luke Baxter PhD","doi":"10.1002/jcph.70036","DOIUrl":"10.1002/jcph.70036","url":null,"abstract":"<p>Systematic reviews hold significant academic weight, but poor execution can render them misleading and unreliable. To help improve the quality of systematic reviews, the peer review process plays a crucial role. Peer reviewing systematic reviews requires a distinct skill set compared to reviewing primary research studies. Systematic reviews differ in their methodology and reporting standards, necessitating a structured approach to evaluation. This commentary offers guidance on best practice when peer reviewing systematic reviews, with an emphasis on synthesis of quantitative data from clinical trials. In this article, nine key topics are covered, namely correct classification of review type, adherence to systematic methods, pre-registration, methodological and reporting quality, search strategy evaluation, risk of bias assessment, evidence synthesis methods, data and code availability, and use of standardized assessment tools. By helping to ensure best practice is followed for each of these topics, peer reviewers can play a crucial role in upholding the methodological integrity of systematic reviews, ensuring they contribute reliable and meaningful evidence to the scientific literature.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 10","pages":"1328-1332"},"PeriodicalIF":0.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005009","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":"Crowdsourcing Proposal Supporting Patient Engagement in Parkinson's Disease: A Digital Research Environment (DRE)-Enabled, Patient Swarm Approach to Develop QSP Models","authors":"Jeffrey S. Barrett PhD,&nbsp;Benedetto Piccoli PhD,&nbsp;Christopher Denaro PhD,&nbsp;Stephan Schmidt PhD,&nbsp;Valvanera Vozmediano PhD,&nbsp;Serge Guzy PhD,&nbsp;Kyle Barrett BS,&nbsp;Kevin Kwok MS,&nbsp;Scott Russell MS,&nbsp;David Sibbald MS","doi":"10.1002/jcph.70028","DOIUrl":"10.1002/jcph.70028","url":null,"abstract":"<p>Seeking to incorporate the patient voice into a collaborative effort to develop a quantitative system pharmacology (QSP) model for Parkinson's disease (PD) we propose the creation of a “patient swarm” in conjunction with a digital research environment (DRE) connecting various academic centers of excellence and their compute environments to promote data sharing and model collaboration with patient engagement. Patients, their advocates, and other stakeholders are welcome to join the crowdsourcing effort with the intention of reading the relevant source literature and contributing thoughts on model priors and model development while sharing their personal disease trajectories. Training materials are provided from experienced modelers and clinical stakeholders and maintained on the DRE as a resource for the “Swarm.” While a number of prominent modelers and clinical stakeholders are part of the initial effort to date, there is an open invitation to the global PD research community to join this effort and help contribute to a solution.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1163-1175"},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020525","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":"Trends in First-in-Human Studies for Intrathecal Antisense Oligonucleotides: Insights From 2010 to 2024","authors":"Natalie Schmitz PharmD, PhD,&nbsp;Mai M. Abdelmageed PhD,&nbsp;Michael Monine PhD,&nbsp;Yan Xu MD, PhD, FCP","doi":"10.1002/jcph.70034","DOIUrl":"10.1002/jcph.70034","url":null,"abstract":"<p>Advancements in antisense oligonucleotide (ASO) therapies have expanded their application to neurological disorders through intrathecal (ASO-IT) delivery into cerebrospinal fluid (CSF). To examine study designs and practices in ASO-IT first-in-human (FIH) trials, we analyzed 29 trials between 2010 and 2024 via a comprehensive review. Most trials targeted rare neurological disorders, with increasing numbers of ASO-ITs advancing to clinical testing over time. Patient populations were predominantly used over healthy participants, with over 50% trials employing randomized controlled designs (3:1 active-to-placebo) while others were open label. Trials commonly start in adults or older children before expanding to younger cohorts. Recent trends reveal increased uses of direct-to-multiple ascending dose strategies and single-patient trials, particularly for rare diseases. Dose escalations typically spanned four cohorts over a 10× dose range, with early escalations up to 4× between adjacent cohorts and smaller increments (1.25-1.5×) in later cohorts. Human dose selection often integrates translational modeling and human equivalent dose approach, scaled by CSF or central nervous system (CNS) tissue volumes. Starting doses prioritized robust safety margins (median 30×) with limited pharmacological activity, while top doses aimed therapeutic benefit with high activity and safety margins ≥1×, with the goal to achieve ≥70%-80% target engagement (e.g., mRNA knockdown) during dose escalation. Dosing intervals, typically 2-4 weeks (up to 12 weeks), reflected ASO-ITs’ prolonged CNS half-life. Adaptive designs enabled real-time dose adjustments upon emerging safety and pharmacokinetics/pharmacodynamic data. This analysis highlights the importance of flexible, personalized, innovative FIH designs, such as single-patient studies, and model-informed strategies to advance ASO-IT development for rare neurological diseases.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1065-1075"},"PeriodicalIF":0.0,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002394","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 Retrospective Analysis of PK and Response of Oral Ibuprofen in the Treatment of a Patent Ductus Arteriosus in Extremely Low Gestational Age Neonates","authors":"Mohd Asif MD,&nbsp;Katelyn Sushko PhD,&nbsp;Abdul Razak MD,&nbsp;Sayem Borhan PhD,&nbsp;Michael Rieder MD, PhD,&nbsp;John van den Anker MD, PhD,&nbsp;Samira Samiee-Zafarghandy MD","doi":"10.1002/jcph.70033","DOIUrl":"10.1002/jcph.70033","url":null,"abstract":"<p>Oral ibuprofen is the preferred pharmacotherapeutic option for treatment of a persistent patent ductus arteriosus (PDA), but evidence for its optimal use in extremely low gestational age newborns (ELGANs) remains limited. In the current study, we aimed to investigate the pharmacokinetics and exposure-response relationship of oral ibuprofen in ELGANs of ≤72 h postnatal age (PNA) on standard (SD) versus those &gt;72 h PNA on high-dose (HD) regimen for closure of persistent PDA. This was a retrospective analysis of data from a previous population PK study of ELGANs with a persistent PDA treated with a SD (10–5–5 mg/kg/day, PNA &lt;72 h) versus a HD (20–10–10 mg/kg/day, PNA &gt;72 h) oral ibuprofen, with the primary aim of comparing degree of exposure, defined as AUC_0-24 (AUC from time 0 to 24 h). Twelve ELGANs received SD versus 11 receiving HD oral ibuprofen. The mean (SD) of exposure at 24 h (AUC_{0-24 h}) was 486 (128) and 509 (208) (<i>P</i> = .41) and at 72 h (AUC_{0-72 h}) was 1529 (493) and 1510 (820) (<i>P</i> = .94). Two (16%) ELGANs in the HD group developed severe gastrointestinal (GI) AEs and 1 (9%) in the SD had severe intraventricular hemorrhage. The use of SD and HD oral ibuprofen in ELGANs with PNA of &lt;72 h and those &gt;72 h, respectively, resulted in comparable exposure. The PNA-dependent response to oral ibuprofen and exposure-response relationship in ELGANs of higher PNA needs further investigation.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1157-1162"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991921","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":"Pediatric Developmental Drug Toxicity: Description of Juvenile Animal Studies in US FDA Prescribing Information and Assessing the Need for New Approach Methodologies","authors":"Gelareh Abulwerdi PhD,&nbsp;Hillary Nguyen PharmD,&nbsp;Sherbet Samuels PhD,&nbsp;Elizabeth Hahn PharmD,&nbsp;Nina Smikh PharmD,&nbsp;Robert Nadeau PhD,&nbsp;Dionna J. Green MDFCP,&nbsp;Gilbert J. Burckart PharmD, FCP","doi":"10.1002/jcph.70030","DOIUrl":"10.1002/jcph.70030","url":null,"abstract":"<p>Currently juvenile animal studies (JAS) are the standardized way for pediatric preclinical developmental safety assessments. With advancement of new approach methodologies (NAMs) and reduced animal testing that can add to JAS findings, the assessment of the prior outcome of JAS in pediatric drug development is essential. The objectives of this study were to (a) identify, extract, and analyze JAS studies from the prescribing information (PIs) of approved pediatric products, and (b) assess the results which were obtained through those JAS studies in relation to the latest guidance. This study identified 74 approved pediatric drug products with JAS described on the PIs. For JAS, 83.8% included one species with rats being the most common. The weight of evidence approach, outlined in the S11 Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals Guidance, considers two objective criteria that can be easily assessed from PIs: youngest intended pediatric age and the clinical treatment duration. More than half of the products (64.9%) were intended for children and adolescents, and about half of the products (51.4%) were intended for acute or single use. JAS produced a warning added in the pediatric use section of the PIs in only 8.1% (6/74) of approved pediatric products. NAMs are being developed in areas such as secondary targets, developmental genetics, microphysiologic systems, and quantitative systems pharmacology modeling, all of which can compliment JAS for developmental safety assessments. So while JAS can contribute to pediatric preclinical safety assessment, the development of NAMs should be further explored.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1150-1156"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038800","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":"Clinical Pharmacology Guidances Advancing Drug Development and Regulatory Assessment: Role and Opportunities","authors":"Anuradha Ramamoorthy PhD, FCP,&nbsp;Daphne Guinn PhD,&nbsp;Elimika Pfuma Fletcher PharmD, PhD,&nbsp;Michael Pacanowski PharmD, MPH,&nbsp;Kellie Reynolds PharmD,&nbsp;James Polli PhD,&nbsp;Rajanikanth Madabushi PhD","doi":"10.1002/jcph.70029","DOIUrl":"10.1002/jcph.70029","url":null,"abstract":"&lt;p&gt;Clear and pragmatic scientific recommendations from regulators promote consistent and timely generation of quality data during drug development leading to more efficient regulatory review. To provide these scientific recommendations, the Office of Clinical Pharmacology (OCP) within the US Food and Drug Administration (FDA) has adopted a lifecycle approach to guidance and policy development.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This end-to-end process provides a structured approach for identification, development, clearance, implementation, and evaluation of guidances and policies, and facilitates modernization of existing guidances and policies or development of de novo guidances and policies in an informed manner in an ever-changing scientific landscape (Figure 1). In the multidisciplinary field of clinical pharmacology, such an approach is important to ensure that guidances and policies are relevant, contemporary, and informed by accumulated scientific and regulatory experience. The goals are to enable innovation in drug development, ensure consistency in decision-making, and protect health and safety of real-world patients and research participants.&lt;/p&gt;&lt;p&gt;Developing and updating clinical pharmacology guidances benefits from proactive engagement of all the interested parties within the ecosystem of drug development, regulatory assessment, and patient care. As part of engagement efforts, OCP published a federal register notice and conducted a public workshop to identify emerging scientific topics that might benefit from further scientific research and best practice development.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Herein, we highlight the discussions from the “Clinical Pharmacology Guidances Advancing Drug Development and Regulatory Assessment: Role and Opportunities” workshop conducted as part of a collaboration between OCP and the University of Maryland Center for Excellence in Regulatory Science and Innovation (MCERSI) on May 8–9, 2024. The discussions focused on five areas: specific patient populations, rare diseases, drug lifecycle management, application of quantitative approaches, and value of globally harmonized clinical pharmacology guidelines. The workshop highlighted current guidances relevant to the field of clinical pharmacology, discussed the challenges and gaps in applying clinical pharmacology principles during drug development, and identified potential opportunities for further regulatory research and best practice development. Outlined below and in Figure 2 are some of the challenges and opportunities identified by the discussants.&lt;/p&gt;&lt;p&gt;“Specific patient populations” typically refers to subgroups of patients who may require additional considerations to optimize therapy based on potential differences in drug disposition or response, and may include subpopulations such as older adults, children, those with organ impairment, and pregnant or lactating females. While several regulatory guidances are dedicated to generating data and prescribing recom","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1176-1180"},"PeriodicalIF":0.0,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/jcph.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044205","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":"Quantifying the Effect of Posaconazole on Venetoclax Metabolism in Chinese Patients With Hematologic Diseases","authors":"Wenli Sun MS,&nbsp;Lei Wang MD,&nbsp;Hai He MD,&nbsp;Gen Wang MD,&nbsp;Meng Li BS,&nbsp;Yang Xue BS,&nbsp;Jing Xing EMBA,&nbsp;Jian Cheng MD,&nbsp;Hongxing Liu MD","doi":"10.1002/jcph.70025","DOIUrl":"10.1002/jcph.70025","url":null,"abstract":"<p>Venetoclax (Ven) and posaconazole (PSZ) are commonly co-administered in patients with hematological diseases, including acute myeloid leukemia, chronic lymphocytic leukemia, and other related conditions. Due to CYP3A inhibition by PSZ, Ven plasma concentrations (ConcVen) are elevated, necessitating dose adjustments. This study aimed to quantitatively characterize the relationship between PSZ exposure and Ven pharmacokinetics through retrospective analysis of data from hematological patients receiving concurrent therapy. We examined correlations between ConcVen (both absolute and normalized by daily dose [ConcVen/DD]) and PSZ exposure metrics (daily dose and plasma concentrations [ConcPSZ]) using Spearman's analysis. A population pharmacokinetic model incorporating an innovative rectified linear unit-like function was developed to quantify the nonlinear interaction between these drugs and characterize Ven disposition, providing a more precise mathematical description of their relationship. This was followed by Monte Carlo simulations to predict steady-state peak concentrations across various dosing scenarios and PSZ exposure concentrations. The analysis included 461 paired Ven–PSZ concentration measurements from 282 patients. Significant correlations were observed between both ConcVen and ConcVen/DD versus ConcPSZ (<i>P</i> &lt; .01). Ven pharmacokinetics was best described by a two-compartment model, with clearance showing significant concentration-dependent reduction with increasing ConcPSZ. Simulations demonstrated that Ven doses of 70 and 100 mg daily maintained therapeutic steady-state concentrations. However, careful monitoring of Ven concentrations is warranted when ConcPSZ exceeds 2.5 µg/mL. Based on these findings, we recommend that Ven dose adjustments during concurrent PSZ therapy be guided by therapeutic drug monitoring of both agents, with dosing decisions informed by our population pharmacokinetic model incorporating measured ConcPSZ.</p>","PeriodicalId":22751,"journal":{"name":"The Journal of Clinical Pharmacology","volume":"65 9","pages":"1106-1115"},"PeriodicalIF":0.0,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041892","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}