Clinical Pharmacology in Drug Development最新文献

{"title":"Pacritinib Impact on QT Interval: Results of a Thorough QT Study and Post Hoc Analysis of Prospective Clinical Trial Data","authors":"Sarah A. Buckley,&nbsp;Suliman Al-Fayoumi,&nbsp;James P. Dean,&nbsp;Jessica Zhang,&nbsp;Purvi Suthar,&nbsp;Muriel Richard","doi":"10.1002/cpdd.70070","DOIUrl":"10.1002/cpdd.70070","url":null,"abstract":"<p>Pacritinib, an inhibitor of JAK2/IRAK1/ACVR1 that is devoid of JAK1 activity, approved for treating myelofibrosis in patients with severe thrombocytopenia, carries a label warning for QT interval prolongation. To evaluate the cardiac safety of pacritinib, a randomized, placebo- and active-controlled, single-dose thorough QT (TQT) study was conducted in healthy subjects, and a dose-finding study (PAC203) was conducted in patients with myelofibrosis. In the TQT study, 42 subjects received single doses of pacritinib 400 mg, moxifloxacin 400 mg (positive control), and placebo in a crossover design. The maximal placebo-corrected change in QT interval with pacritinib was −9.7 ms (90% confidence interval: −13.4, −6.1), and all upper confidence bounds were &lt;10 ms. A small, clinically irrelevant inverse concentration–QTc relationship was observed. No subject administered pacritinib had a QTc interval using Fridericia's formula (QTcF) &gt;480 ms or a change from baseline in QTcF &gt;30 ms. Moreover, in the PAC203 trial, there was no correlation between pacritinib exposure and QTcF at weeks 12 or 24. Median QTcF changes from pre-dose to 4 h post-dose were minimal (+2.7 and −0.3 ms, respectively), and no dose–response relationship was identified. These findings suggest that pacritinib exposure is unlikely to be correlated with QT prolongation.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomized Phase 1 Studies Evaluating the Safety, Tolerability, Pharmacokinetics, and Target Occupancy of Zampilimab in Healthy Participants","authors":"Jo Collier,&nbsp;Rowann Bowcutt,&nbsp;Geoffrey I. Johnston,&nbsp;Jane Y. C. Chan,&nbsp;Anastasiia Raievska,&nbsp;Alison Bigley,&nbsp;Richard Nicholl,&nbsp;Tim S. Schmidt,&nbsp;Maria Sarno,&nbsp;Zahid Ali,&nbsp;Elizabeth Thomson","doi":"10.1002/cpdd.70052","DOIUrl":"10.1002/cpdd.70052","url":null,"abstract":"<p>Zampilimab (UCB7858) is a humanized monoclonal immunoglobulin G4P, transglutaminase 2 (TG2) inhibiting antibody. We investigated safety, tolerability, pharmacokinetics, and target occupancy of zampilimab (intravenous ≤2000 mg; subcutaneous ≤1000 mg) in healthy participants in a randomized, placebo‑controlled, single-ascending-dose Phase 1 study (UP0029; NCT02879877). Of 78 participants (58 zampilimab; 20 placebo), treatment-emergent adverse events (TEAEs) occurred in 42 (72.4%) versus 14 (70%), respectively. One participant (intravenous zampilimab 2000 mg) reported a serious TEAE of moderate infusion-related reaction (a protocol-defined stopping criterion), leading to a temporary study hold. Although the reaction resolved within 3 days, and the participant completed follow up, dose-escalation was suspended, and the study terminated. Zampilimab demonstrated dose-proportional, linear pharmacokinetics (t_1/2 17-23 days; subcutaneous bioavailability 77%). TG2 target occupancy in skin directly correlated with serum zampilimab concentration, near-maximal occupancy ≥250 µg/mL, corresponding to intravenous doses ≥1000 mg between Days 2 and 5. A subsequent randomized, placebo‑controlled, Phase 1 study (UP0105; NCT04705350) investigated single intravenous doses of zampilimab (2000 and 3000 mg) at a lower concentration and slower infusion rate versus UP0029, using learnings from the administration strategy. Of 16 participants (12 zampilimab; four placebo), TEAEs occurred in eight (66.7%) versus one (25%), respectively. TEAEs were mild/moderate; none were drug related. No infusion-related reactions occurred. Zampilimab safety profile was acceptable after single intravenous and subcutaneous doses ≤1000 mg (UP0029) and intravenous doses ≤3000 mg (UP0105) following optimization of maximum concentration (10 mg/mL) at an infusion rate of 25 mg/min over 120 min. These studies support the ongoing development of zampilimab.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13170637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148076222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148097307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethnic Bridging of Votoplam, a HTT Gene Splicing Modifier, Using Pharmacokinetic Comparison Between Caucasian and Japanese Subjects","authors":"Lucy Lee,&nbsp;Amy-Lee Richards,&nbsp;Prachi Anand,&nbsp;Brian Beers,&nbsp;Lee Golden,&nbsp;Ronald Kong","doi":"10.1002/cpdd.70062","DOIUrl":"10.1002/cpdd.70062","url":null,"abstract":"<p>Votoplam is a novel, orally bioavailable, small molecule HTT gene splicing modifier that is being developed for the treatment of Huntington's disease. A single-dose, open-label, three-dose level (5, 10, 20 mg), parallel group ethnicity study was conducted to evaluate the pharmacokinetics and safety of votoplam in healthy Caucasian versus Japanese participants. Six participants per ethnic group were enrolled at each dose (12 participants per dose level overall). Thirty-five participants (N = 18 Japanese; N = 17 Caucasian) completed the study. Study results showed slightly higher exposure for Japanese participants at all dose levels. AUC_0–last increased by 1.27-, 1.17-, and 1.29-fold, and C_max increased by 1.58-, 1.19-, and 1.61-fold for 5, 10, and 20 mg, respectively, for Japanese compared with Caucasian participants. Doses proportionality was observed for both ethnicities. Few mild and moderate TEAEs were reported and were comparable between Japanese and Caucasian participants. In summary, votoplam pharmacokinetics and safety profiles are similar between healthy Japanese and Caucasian participants when administered in the single dose range of 5, 10, and 20 mg. Therefore, it is expected that dose adjustments should not be necessary in future clinical studies enrolling Japanese participants.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase 1, Open-Label, Single-Dose Study of the Effect of Hepatic Impairment on the Pharmacokinetics of Erdafitinib, an FGFR Inhibitor","authors":"Wei Zhu,&nbsp;Peter Hellemans,&nbsp;Anna Mitselos,&nbsp;Marc De Meulder,&nbsp;Juhui James Jiao,&nbsp;Hui Tian","doi":"10.1002/cpdd.70061","DOIUrl":"10.1002/cpdd.70061","url":null,"abstract":"<p>Erdafitinib, an oral pan-<i>FGFR</i> inhibitor is extensively metabolized in the liver. This open-label, single-dose, phase 1 study evaluated the pharmacokinetics (PK) of erdafitinib in participants with hepatic impairment versus healthy controls. Overall, 26 participants were enrolled. Following a single 6 mg oral dose, the maximum plasma concentration (C_max) of total erdafitinib was reached at median t_max of 3 h across all groups (participants with mild hepatic impairment, moderate hepatic impairment, and control). The geometric mean ratios for free C_max and free AUC_∞, were 96.07% and 95.22% in participants with mild hepatic impairment compared with controls, respectively. The geometric mean ratios for free C_max and free AUC_∞, were 104.8% and 87.51% in participants with moderate hepatic impairment compared with controls, respectively. Single oral doses of erdafitinib were well tolerated across all cohorts, and no new safety signals were noted. The results demonstrate that dose adjustments are not necessary in participants with mild or moderate hepatic impairment receiving oral erdafitinib.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148097308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148099389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Work Behind the First Dose: How Early Clinical Studies Shape the Course of Drug Development","authors":"Amalia M. Issa PhD, MPH","doi":"10.1002/cpdd.70064","DOIUrl":"10.1002/cpdd.70064","url":null,"abstract":"&lt;p&gt;Recently, during a discussion with graduate students about translational pharmacology, the conversation turned to what many consider a defining milestone in drug development: the first dose administered to a human participant. One student described it as “the moment when years of preclinical research finally meet the clinic.” That description captures the excitement of moving from discovery to clinical investigation.&lt;/p&gt;&lt;p&gt;Yet for clinical pharmacologists, the first dose represents something different. It is not the culmination of a process but the beginning of a series of carefully structured scientific questions.&lt;/p&gt;&lt;p&gt;At the outset of a first-in-human study, the most important questions are only beginning to emerge. What exposure is achieved at the starting dose? How does that exposure vary across individuals? What pharmacodynamic signals begin to appear, and how do they relate to safety or potential efficacy? Just as importantly, how should these early observations inform the next dose, the next study, and the broader development strategy?&lt;/p&gt;&lt;p&gt;Such insights seldom arise from a single experiment. Instead, they emerge through a sequence of carefully designed early-phase investigations. Single-ascending and multiple-ascending dose studies, food-effect evaluations, drug–drug interaction assessments, and studies in special populations collectively establish the pharmacokinetic and pharmacodynamic relationships that guide dose selection and development strategy. Together, these studies begin to define the exposure–response relationships that ultimately shape dosing strategies and inform later-phase clinical trials.&lt;/p&gt;&lt;p&gt;In this sense, early clinical pharmacology provides much of the scientific architecture for drug development. Decisions about dose selection, study design, and development strategy often depend on the careful interpretation of data generated during these early investigations. When successful, the insights gained in Phase I studies echo throughout the entire development program and ultimately influence the information that appears in the prescribing label.&lt;/p&gt;&lt;p&gt;Early clinical pharmacology has become increasingly quantitative. Integrated, model-informed drug development (MIDD) approaches now shape experimental design, bridging preclinical and clinical data to optimize dosing, predict variability, and support regulatory decisions. Population pharmacokinetic modeling, exposure–response analysis, and physiologically based pharmacokinetic simulations place early findings within broader mechanistic frameworks.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Regulatory science has evolved alongside these methodological advances. The International Council for Harmonisation recently finalized Guideline M15, defining general principles for MIDD planning, evaluation, and documentation.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; In parallel, initiatives such as the US Food and Drug Administration's &lt;i&gt;Project Optimus&lt;/i&gt; emphasize early, evidence-based dose optimization","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.70064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Pharmacokinetics and Bioequivalence Assessment of Metformin/Pioglitazone Tablet in Fasting and Fed Conditions: A Randomized Study in Healthy Chinese Subjects","authors":"Hongcheng Li,&nbsp;Mengke Li,&nbsp;Bin Liu,&nbsp;Zijie Wei,&nbsp;Lulu Chen,&nbsp;Chao Li,&nbsp;Qing Fang,&nbsp;Xintong Wang,&nbsp;Ling Zhou,&nbsp;Dongsheng Ouyang,&nbsp;Xiaohui Li","doi":"10.1002/cpdd.70063","DOIUrl":"10.1002/cpdd.70063","url":null,"abstract":"<p>Metformin/pioglitazone tablets are a fixed-dose combination of metformin hydrochloride and pioglitazone. In healthy Chinese subjects, this study evaluated the pharmacokinetics and bioequivalence of metformin/pioglitazone (500/15 mg) tablets. We conducted a single-center, open-label, randomized, two-way crossover study in which subjects were randomized in a 1:1 ratio to either the test formulation or the reference formulation, separated by a 10-day washout period. Blood samples collected at pre-arranged intervals before and after dosing were analyzed using validated liquid chromatography-tandem mass spectrometry techniques to determine metformin and pioglitazone plasma concentrations. Finally, subjects completed fasting and fed studies, respectively. In both studies, the 90% confidence intervals for the geometric mean ratios (test/reference) of C_max, AUC_0–t, and AUC_0–∞ were within acceptable bioequivalence limits (0.80–1.25), and no serious adverse events were observed. The study demonstrated that the tested and reference formulations of metformin/pioglitazone tablets are bioequivalent and well tolerated under both fasting and fed conditions.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}