Clinical Pharmacology in Drug Development最新文献

{"title":"A pharmacokinetics study to evaluate drug–drug interactions between fipaxalparant and concomitant medications in healthy participants","authors":"Yang Song,&nbsp;Krischan Hudson,&nbsp;Zhan Ye,&nbsp;Lisa Hawley,&nbsp;Brajesh Pandey,&nbsp;Jennifer Zarzoso,&nbsp;John Rogowski,&nbsp;Yajing Sun,&nbsp;William A. Rees,&nbsp;Yan Xin","doi":"10.1002/cpdd.1621","DOIUrl":"10.1002/cpdd.1621","url":null,"abstract":"<p>Fipaxalparant, a small molecule and negative allosteric modulator of lysophosphatidic acid receptor 1, is being evaluated in phase 2 clinical trials of idiopathic pulmonary fibrosis (IPF) and diffuse cutaneous systemic sclerosis. This phase 1, open-label, crossover, 3-cohort study in healthy adults evaluated mutual drug–drug interactions (DDIs) between fipaxalparant and the IPF medications pirfenidone and nintedanib, as well as the effects of itraconazole (P-glycoprotein inhibitor) and rifampin (potent organic anion transporting polypeptide [OATP] inhibitor) on fipaxalparant. Participants received a single oral dose of fipaxalparant 300 mg. Overall, 16, 20, and 15 participants completed the study in cohorts 1, 2, and 3, respectively. The study demonstrated no relevant mutual DDIs between fipaxalparant and pirfenidone/nintedanib at clinical doses. There was no effect of itraconazole 400 mg on fipaxalparant exposure. A single rifampin 600 mg dose caused 1.48-fold and 1.86-fold increases in fipaxalparant <i>C</i>_max and AUC_0–∞, respectively. Treatment-emergent adverse events were mild/moderate with fipaxalparant alone or with the other study drugs. Overall, fipaxalparant absorption in vivo occurs independently of the P-glycoprotein–mediated gut efflux pathway, and fipaxalparant is a clinically relevant OATP substrate. Results of this DDI study will inform the management of concomitant medications of ongoing/future trials of fipaxalparant.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548571","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":"Pharmacokinetics and Bioequivalence of Ilaprazole Enteric-Coated Tablets in Healthy Chinese Volunteers: A Two-Sequence, Four-Period, Fully Replicated Crossover Study","authors":"Lijie Du,&nbsp;Yi Zhang,&nbsp;Fangliang Gan,&nbsp;Jiamin Yang,&nbsp;Li Li","doi":"10.1002/cpdd.1628","DOIUrl":"10.1002/cpdd.1628","url":null,"abstract":"<p>Ilaprazole enteric-coated tablets are a novel proton pump inhibitor primarily used for the treatment of gastroesophageal reflux disease, with metabolism not affected by CYP2C19 genetic polymorphism. This study evaluated the pharmacokinetics and bioequivalence of two formulations of ilaprazole enteric-coated tablets in Chinese healthy volunteers under fasting and fed conditions using a single-center, randomized, open-label, single-dose, two-formulation, four-period, two-sequence, fully replicated crossover design. A total of 72 volunteers were enrolled, with 36 in each group. In the fasting group, volunteers received a single dose of 5 mg of the test or reference formulation in each period, while in the fed group, a high-fat meal was consumed 30 min before drug administration. Blood samples were collected within 36 h postdose, and plasma concentrations of ilaprazole were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. The geometric means and 90% confidence intervals of AUC_0–t, AUC_0–∞, and C_max for both fasting and fed conditions were within the 80%–125% bioequivalence range, and the upper limit of the one-sided 95% confidence interval was ≤0. Both formulations demonstrated bioequivalence under these conditions, with no serious adverse reactions observed.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630701","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":"Correction to “Preclinical and Phase 1 Assessment of Antisense Oligonucleotide Bepirovirsenin Hepatitis B Virus–Transgenic Mice and Healthy Human Volunteers: Support for Clinical Dose Selection and Evaluation of Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses”","authors":"","doi":"10.1002/cpdd.1620","DOIUrl":"10.1002/cpdd.1620","url":null,"abstract":"<p>Han K, Theodore D, McMullen G, et al. Preclinical and phase 1 assessment of antisense oligonucleotide bepirovirsen in hepatitis B virus–transgenic mice and healthy human volunteers: support for clinical dose selection and evaluation of safety, tolerability, and pharmacokinetics of single and multiple doses. <i>Clin Pharmacol Drug Dev</i>. 2022;11:1191–1202. https://doi.org/10.1002/cpdd.1154</p><p>In the article cited above, the authors have determined that an error was present in the Funding section. The corrected Funding section is shown below.</p><p>Funding</p><p>This phase 1 first-in-human study was, at the time of the trial, fully sponsored and funded by Ionis Pharmaceuticals, Inc. (ISIS 50538-CS1). The study has since been acquired by GSK (Study 213725). The preclinical in vitro and in vivo studies (3470-144) were sponsored and funded by Ionis Pharmaceuticals Inc. and supported by a grant from the National Institutes of Health to Stefan Wieland (AI094409).</p><p>We apologize for this error.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1620","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145376362","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":"Comparison of Efficacy and Safety Profiles Between Omadacycline and Moxifloxacin in Elderly Patients with Community-Acquired Pneumonia: A Randomized, Controlled Trial","authors":"Muming Yu,&nbsp;Xiaorong Wang,&nbsp;Sitong Wu,&nbsp;Zikang Zhou,&nbsp;Yancun Liu,&nbsp;Yanfen Chai","doi":"10.1002/cpdd.1627","DOIUrl":"10.1002/cpdd.1627","url":null,"abstract":"<p>Omadacycline is a novel aminomethylcycline antibiotic that shows non-inferior efficacy to moxifloxacin in adults with community-acquired pneumonia (CAP), but lacking clinical evidence in elderly patients with CAP. This randomized, controlled study aimed to investigate the efficacy and safety of omadacycline in elderly patients with CAP. Eligible elderly patients with CAP were randomized at a 1:1 ratio to the omadacycline group (n = 48) and moxifloxacin group (n = 49) to receive the corresponding agent. The primary endpoint was clinical response. The most common pathogens in the omadacycline and moxifloxacin groups were <i>viridans streptococci</i> (16.7%, 16.3%), <i>Klebsiella pneumoniae</i> (14.6%, 14.3%), and <i>Neisseria sicca</i> (14.6%, 14.3%). Clinical response rate was greater in the omadacycline group compared to the moxifloxacin group (54.2% vs 26.5%, <i>P</i> =  .032). The omadacycline group showed higher significant improvement rate (41.7% vs 16.3%, <i>P</i> =  .02), but similar complete recovery (12.5% vs 10.2%, <i>P</i> =  .737), effective improvement (37.5% vs 59.2%, <i>P</i> =  .125), and ineffectiveness (8.3% vs 14.3%, <i>P</i> =  .384) rates compared to the moxifloxacin group. Results of C-reactive protein, procalcitonin, and interleukin-6 at baseline and after treatment, as well as their changes did not vary between the omadacycline and moxifloxacin groups (all <i>P</i> &gt;  .05). No difference was observed in liver, kidney, and coagulation function parameters between the two groups (all <i>P</i> &gt;  .05). Omadacycline indicates greater treatment efficacy and comparable safety profiles versus moxifloxacin in elderly patients with CAP.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562620","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":"Integrating Pharmacogenomic Insights in GLP-1 Receptor Agonist Therapy: Direct GLP1R and ARRB1 Variants and Indirect CYP2D6 Influences in Personalized Obesity Management","authors":"Navodi Sandamini Jayathilaka,&nbsp;Arunodya Vishwanthi Weththasinghe,&nbsp;Nila Ganamurali,&nbsp;Sarvesh Sabarathinam","doi":"10.1002/cpdd.1624","DOIUrl":"10.1002/cpdd.1624","url":null,"abstract":"<p>Glucagon-like peptide-1 (GLP-1) receptor agonists have become frontline agents in obesity treatment due to their efficacy. However, there is considerable inter-individual variability in treatment response. Although these agents are primarily degraded by proteolytic enzymes rather than cytochrome P450 (CYP) pathways, pharmacogenomic factors may indirectly influence therapeutic outcomes. This review investigates the role of CYP2D6 polymorphisms in optimizing GLP-1 receptor agonist therapy in obesity. It explores genetic influences on treatment variability and highlights the importance of personalized dosing strategies. A systematic search of PubMed, Embase, and Web of Science (1990-2025) was conducted using terms such as “CYP2D6 polymorphisms,” “GLP-1 receptor agonists,” “pharmacogenomics,” and “personalized medicine.” Emphasis was placed on primary experimental studies. While GLP-1RAs are not CYP2D6 substrates, pharmacogenomic factors play a key role through indirect mechanisms. ARRB1 (rs140226575 and Thr370Met) and GLP1R (rs6923761 and Gly168Ser) variants affect glycemic response. CYP2D6 polymorphisms significantly influence metabolism of concomitant medications (e.g., antidepressants and beta-blockers), affecting efficacy and safety. Ethnic variability in CYP2D6 allele frequencies further underscores the need for tailored approaches. Integrating pharmacogenomic data, including CYP2D6 status, can support personalized obesity management and improve clinical outcomes. The primary metabolizers of GLP-1 receptor agonists are proteolytic enzymes; nevertheless, pharmacogenomic heterogeneity influences treatment results via both direct and indirect mechanisms. Variants in CYP2D6 polymorphisms have an indirect impact on treatment outcomes through changed metabolism of concurrent drugs including beta-blockers and antidepressants, while variations in GLP1R and ARRB1 directly affect receptor signaling and weight loss effectiveness.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522661","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":"Pharmacokinetic Comparison Between a Fixed-Dose Combination of Atorvastatin/Fenofibrate 20/145 mg and the Corresponding Individual Components","authors":"Seungri Lee,&nbsp;Juyoung Khwarg,&nbsp;Sungyeun Bae,&nbsp;Dong-Min Park,&nbsp;Heejung Park,&nbsp;SeungHwan Lee,&nbsp;Kyung-Sang Yu","doi":"10.1002/cpdd.70043","DOIUrl":"10.1002/cpdd.70043","url":null,"abstract":"<p>Co-administration of atorvastatin and fenofibrate has demonstrated clinical benefits in patients with dyslipidemia. To improve convenience and adherence, a fixed-dose combination (FDC) of the two agents has gained interest. This study aimed to compare the pharmacokinetics (PKs) and safety of an FDC of atorvastatin/fenofibrate 20/145 mg with the corresponding individual components. A randomized, open-label, single-dose, two-sequence, two-treatment, four-period full replicated crossover study was conducted. Participants were randomly assigned to one of the two sequences and received FDC or individual components. PK parameters were estimated using a non-compartmental method. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the individual components were calculated using mixed effect model. A total of 36 participants completed the study. The GMRs (90% CIs) for maximum plasma concentration and area under the time-concentration curve from zero to the last measurable point were 1.1038 (0.9985-1.2202) and 1.0148 (0.9745–1.0567) for atorvastatin, 1.0032 (0.9261-1.0867) and 0.9882 (0.9520–1.0258) for 2-OH atorvastatin. For fenofibric acid, the corresponding values were 0.9896 (0.8810-1.1116) and 0.9871 (0.8869-1.0986), respectively. The FDC of atorvastatin/fenofibrate 20/145 mg showed comparable PK profiles to the corresponding individual components, supporting its potential as an alternative therapeutic option for dyslipidemia with convenience.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12996741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147389734","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 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148072938","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":"Bioequivalence Study of Two Olopatadine Hydrochloride Tablets in Chinese Healthy Subjects Under Fasting and Fed Conditions","authors":"Yuyan Lei,&nbsp;Fang Pei,&nbsp;Qingqi Wu,&nbsp;Guiling Xiong,&nbsp;Fengzhi Liu,&nbsp;Xintong Wang,&nbsp;Lulu Chen,&nbsp;Chao Li,&nbsp;Ling Zhou,&nbsp;Qing Fang,&nbsp;Weiming Chen,&nbsp;Dongsheng Ouyang,&nbsp;Xiaohui Li","doi":"10.1002/cpdd.1629","DOIUrl":"10.1002/cpdd.1629","url":null,"abstract":"<p>Olopatadine hydrochloride, a second-generation selective histamine H1 receptor antagonist, is an effective anti-allergic agent. This study evaluated the pharmacokinetics and bioequivalence of two olopatadine hydrochloride tablet formulations in healthy Chinese subjects under fasting (n = 24) and fed (n = 24) conditions. A single-center, randomized, open-label, single-dose, two-way crossover study was conducted, in which 48 subjects were randomized to receive 5 mg of the test or reference formulation, followed by a 7-day washout period. Blood samples were collected at predefined intervals up to 24 h post-dose, and olopatadine plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. The results demonstrated no significant differences in the pharmacokinetic profiles between the test and reference formulations under fasting or fed conditions. The 90% confidence intervals (CIs) for the ratio of geometric means of C_max, AUC_0–t, and AUC_0–∞ of olopatadine hydrochloride under both conditions were within the bioequivalence range of 0.80–1.25. A high-fat diet delayed olopatadine hydrochloride absorption, leading to a reduction in C_max to approximately 60% of the fasting value and a decrease in AUC to 85%–90%. No serious adverse events occurred, and safety profiles were comparable between formulations. This research confirmed the bioequivalence and similar safety of the generic olopatadine hydrochloride tablets to the reference formulation.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548577","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":"Results of a Phase 1 Study Assessing the Effect of CIN-102, a Novel Formulation of the Dopamine Receptor Antagonist Domperidone Designed to Treat Gastroparesis, on Cardiac Repolarization in Healthy Volunteers","authors":"Mary Bond,&nbsp;Brian Murphy,&nbsp;Brendan Doran,&nbsp;Borje Darpo,&nbsp;Hongqi Xue,&nbsp;Leela Vrishabhendra,&nbsp;Jon Isaacsohn","doi":"10.1002/cpdd.70039","DOIUrl":"10.1002/cpdd.70039","url":null,"abstract":"<p>CIN-102 is a deuterated form of domperidone in development for the treatment of acute, recurrent gastroparesis. This thorough QT study assessed the effects of CIN-102 on cardiac repolarization in 62 healthy volunteers. In this 4-period randomized crossover study, participants were administered single doses of 30-mg CIN-102 (representing therapeutic exposures), 100-mg CIN-102 (representing supratherapeutic exposures), placebo, and moxifloxacin (positive control). Continuous 12-lead electrocardiograms (ECGs) and time-matched blood samples were collected to determine plasma levels of deuterated domperidone and its major metabolites. The primary endpoint was placebo-corrected change-from-baseline QTc corrected by Fridericia's formula (ΔΔQTcF). By-time-point and concentration-QTc analyses excluded an effect on ΔΔQTcF exceeding 10 ms for both doses of CIN-102 at all time points up to deuterated domperidone plasma concentrations of ≈92  ng/mL (≈6 times the therapeutic steady-state concentration). There were no clinically relevant effects of CIN-102 on heart rate or cardiac conduction, and no deaths or serious adverse events occurred. This thorough QT study demonstrated that at doses producing therapeutic and supratherapeutic exposures, CIN-102 does not have a clinically meaningful effect on ECG parameters, including QT interval. This modified formulation of domperidone provides a potential gastroparesis treatment while decreasing the risk of QT prolongation associated with the traditional formulation of domperidone.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"15 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12969247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375933","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 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148072736","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}