Clinical Pharmacology in Drug Development最新文献_第2页

A 2-Part, Open-Label, Phase 1 Bioequivalence and Food-Effect Study of Ubrogepant in Healthy Adult Participants. 一项2部分、开放标签、i期研究：ubrogeagent在健康成人中的生物等效性和食物效应。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-10 DOI: 10.1002/cpdd.1546

Ramesh Boinpally, Joel M Trugman

{"title":"A 2-Part, Open-Label, Phase 1 Bioequivalence and Food-Effect Study of Ubrogepant in Healthy Adult Participants.","authors":"Ramesh Boinpally, Joel M Trugman","doi":"10.1002/cpdd.1546","DOIUrl":"https://doi.org/10.1002/cpdd.1546","url":null,"abstract":"This Phase 1 study of ubrogepant was conducted to establish the bioequivalence (BE) of the 50- and 100-mg to-be-marketed (TBM) tablet formulations with the clinical trial (CT) 100-mg tablet formulation and evaluate the food effect on the bioavailability of the 100-mg TBM tablet. This 2-part study enrolled healthy participants aged 18-45 years. Part A assessed BE following a single dose of TBM versus CT tablets. Part B evaluated the impact of a high-fat meal on ubrogepant pharmacokinetics. Safety and tolerability were assessed along with standard pharmacokinetic parameters. In Part A (n = 47), the geometric mean ratio and 90% confidence intervals for maximum plasma drug concentration, area under the plasma concentration-time curve (AUC) from time zero to time t, and AUC from time zero to infinity for the TBM and CT formulations demonstrated BE. The time to peak exposure was the same for both formulations. In Part B (n = 18), a high-fat meal delayed time to peak exposure and reduced maximum plasma drug concentration by 22%, with no effect on AUC. The occurrence of treatment-emergent adverse events was low, and the majority were mild. Ubrogepant TBM and CT tablets (1 × 100 mg or 2 × 50 mg) were bioequivalent under fasted conditions, and a high-fat meal had no clinically relevant effect on the bioavailability of the TBM tablet formulation.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985730","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}

引用次数: 0

Effect of Cytochrome P450 3A Inhibition and Induction by Itraconazole and Rifampin on Tazemetostat Pharmacokinetics in Patients With Advanced Malignancies. 伊曲康唑和利福平抑制和诱导细胞色素P450 3A对晚期恶性肿瘤患者他泽美他汀药动学的影响

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-10 DOI: 10.1002/cpdd.1543

Yingxue Chen, Renli Teng, Attila Szanto, Apoorva Kapopara, Rajat Bannerji, Julien Ogier, Devalingam Mahalingam

{"title":"Effect of Cytochrome P450 3A Inhibition and Induction by Itraconazole and Rifampin on Tazemetostat Pharmacokinetics in Patients With Advanced Malignancies.","authors":"Yingxue Chen, Renli Teng, Attila Szanto, Apoorva Kapopara, Rajat Bannerji, Julien Ogier, Devalingam Mahalingam","doi":"10.1002/cpdd.1543","DOIUrl":"https://doi.org/10.1002/cpdd.1543","url":null,"abstract":"This study (NCT04537715) investigated itraconazole (strong cytochrome P450 [CYP] 3A inhibitor) and rifampin (strong CYP3A inducer) on tazemetostat pharmacokinetics. In Part 1, patients received tazemetostat 400 mg orally on Days 1, 15, and 36, and 400 mg twice daily on Days 3-14 and Days 21-35. Itraconazole 200 mg orally once daily was administered on Days 18-38. In Part 2, patients received tazemetostat 800 mg orally once daily on Days 1, 15, and 24, and 800 mg twice daily on Days 3-14 and Days 17-23. Rifampin 600 mg orally once daily was administered on Days 17-25. Twenty-one patients in each part completed had plasma concentrations quantified for pharmacokinetic assessments. Itraconazole coadministration resulted in higher tazemetostat exposures after single doses (Day 21/Day 1) and steady state (Day 36/Day 15). Compared with tazemetostat alone, itraconazole increased mean maximum plasma concentration (Cmax) and area under the concentration-time curve from time 0 to 12 hours (AUC0-12h) by 2.00- and 3.12-fold, respectively, after single doses. Following twice-daily dosing, itraconazole increased mean steady-state Cmax and AUC0-12h by 1.86- and 2.47-fold, respectively. Rifampin coadministration decreased tazemetostat steady-state (Cmax) and AUC0-12h by approximately 84% (Day 24/Day 15). Itraconazole increased tazemetostat exposure by 2-3-fold, and rifampin decreased tazemetostat exposure by 84%, indicating that coadministration of tazemetostat with strong CYP3A inhibitors or inducers should be avoided.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987040","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}

引用次数: 0

A Randomized, Open-Label, Two-Sequence, Crossover Trial Evaluating the Bioequivalence, and Pharmacokinetics of Two Sulfamethoxazole/Trimethoprim Tablet Formulations in Healthy Chinese Volunteers Under Fasting Conditions. 一项随机、开放标签、双序列、交叉试验，评估两种磺胺甲恶唑/甲氧苄啶片制剂在健康中国志愿者空腹条件下的生物等效性和药代动力学。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-05-06 DOI: 10.1002/cpdd.1537

Xueqiong Peng, Yuan Liu, Hongcheng Li, Yuyan Lei, Fangliang Gan, Yusi Wu, Xiaohui Li, Yusheng Zhou

{"title":"A Randomized, Open-Label, Two-Sequence, Crossover Trial Evaluating the Bioequivalence, and Pharmacokinetics of Two Sulfamethoxazole/Trimethoprim Tablet Formulations in Healthy Chinese Volunteers Under Fasting Conditions.","authors":"Xueqiong Peng, Yuan Liu, Hongcheng Li, Yuyan Lei, Fangliang Gan, Yusi Wu, Xiaohui Li, Yusheng Zhou","doi":"10.1002/cpdd.1537","DOIUrl":"https://doi.org/10.1002/cpdd.1537","url":null,"abstract":"The compound sulfamethoxazole (SMZ)/trimethoprim (TMP), a dual-agent formulation comprising SMZ and TMP, exhibits synergistic bacteriostatic and bactericidal activity by disrupting folate metabolism pathways. This study assessed the bioequivalence (BE) of a generic compound SMZ/TMP tablet versus its innovator counterpart under fasting conditions (n = 24). In a meticulous, single-site, randomized, open-label, 2-period, 2-sequence crossover trial, 24 healthy Chinese adults were allocated to receive a single administration of either the test or reference medication, with a 7-day interval between doses. Venous blood samples were obtained pre-dose and at intervals up to 48 hours postdose for subsequent analysis. The plasma levels of SMZ and TMP were determined using a validated ultra-performance liquid chromatography-tandem mass spectrometry technique. Safety monitoring was conducted with precision throughout the trial for all subjects. The study's results indicated no significant differences in the peak plasma concentrations (Cmax) of the drug when comparing the 2 SMZ/TMP formulations. Furthermore, the 90% confidence intervals for the ratios of the geometric means of Cmax, the area under the curve from 0 time to the last quantifiable concentration point (AUC0-t), and the area under the curve extrapolated to an infinite time point (AUC0-∞) were all within the BE range accepted as 80%-125%. Notably, there were no reports of severe adverse events. These outcomes demonstrate the BE and favorable tolerability of the generic compound SMZ/TMP tablet in healthy Chinese subjects.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994481","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}

引用次数: 0

First-in-Human Phase 1 Study to Evaluate the Clinical Pharmacology Properties of RBN-3143, a Novel Inhibitor of Mono-Adenosine Diphosphate Ribosyltransferase-PARP14. 一种新型单腺苷二磷酸核糖基转移酶parp14抑制剂RBN-3143的临床药理学特性的首次人体i期研究

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-04-30 DOI: 10.1002/cpdd.1539

Thomas M Polasek, Alexandra Cole, Viviana Bozón, Erika Manyak, Jonathan Novak, Barbara Yang, Briohny A Johnston, Sudha Parasuraman, Kushal J Paneliya, Virna Schuck

{"title":"First-in-Human Phase 1 Study to Evaluate the Clinical Pharmacology Properties of RBN-3143, a Novel Inhibitor of Mono-Adenosine Diphosphate Ribosyltransferase-PARP14.","authors":"Thomas M Polasek, Alexandra Cole, Viviana Bozón, Erika Manyak, Jonathan Novak, Barbara Yang, Briohny A Johnston, Sudha Parasuraman, Kushal J Paneliya, Virna Schuck","doi":"10.1002/cpdd.1539","DOIUrl":"https://doi.org/10.1002/cpdd.1539","url":null,"abstract":"RBN-3143 is an inhibitor of PARP14 in development for inflammatory diseases. Multiple assessments were conducted to evaluate the clinical pharmacology properties of RBN-3134. A randomized, double-blind, placebo-controlled study assigned healthy volunteers (HVs) to single ascending doses (SADs) (25-1000 mg) or multiple ascending doses (MADs) (150, 300, and 500 mg twice daily [BID] for 14 days) of RBN-3143 or placebo. An open-label, randomized, 3-period, cross-over study evaluated the effects of food and pantoprazole (40 mg once daily [QD]) on the pharmacokinetics of RBN-3143 (500 mg), and a pharmacokinetic drug-drug interaction study with oral midazolam (2 mg) determined whether RBN-3143 (300 mg BID for 14 days) is an inducer of cytochrome P4503A4 (CYP3A4). The most common treatment-related treatment-emergent adverse events in subjects taking RBN-3143 were headache, nausea, vomiting, and elevated serum creatinine. In the SAD, RBN-3143 Cmax and AUCinf increased with dose, and Tmax was 2 hours. RBN-3143 was cleared from plasma with an apparent terminal half-life ranging from 3 to 11 hours. In the MAD, Cmax and AUCinf increased 1.5- and 1.6-fold, respectively, following 14 days of 150, 300, and 500 mg BID dosing. Dosing of RBN-3143 with food resulted in higher Cmax and AUCinf ratios of 1.74 and 1.42, respectively. Coadministration with pantoprazole did not impact RBN-3143 exposure. RBN-3143 was an inducer of CYP3A4 in most but not all subjects, with mean midazolam Cmax and AUCinf ratios of 0.92 and 0.88, respectively. The clinical pharmacology properties of RBN-3143 in HVs support further development for inflammatory diseases.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971493","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}

引用次数: 0

A Randomized Phase 1 Study Evaluating Pharmacokinetics, Safety, and Tolerability of a High-Concentration, Long-Acting Cabotegravir Formulation in Adults Without HIV. 一项评估高浓度长效卡博特韦制剂在无HIV成人中的药代动力学、安全性和耐受性的随机i期研究。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-04-29 DOI: 10.1002/cpdd.1538

Kelong Han, Paul Benn, Jörg Sievers, David Dorey, Michael Warwick-Sanders, Randa Hareedy, Louise Harkness, Claudia Leemereise, Kjersten Offenbecker, Christina Donatti, Darin B Brimhall, Christian Schwabe, Craig Boyle, Michael A Hassman, Steve Knowles, Ronald D'Amico, William R Spreen

{"title":"A Randomized Phase 1 Study Evaluating Pharmacokinetics, Safety, and Tolerability of a High-Concentration, Long-Acting Cabotegravir Formulation in Adults Without HIV.","authors":"Kelong Han, Paul Benn, Jörg Sievers, David Dorey, Michael Warwick-Sanders, Randa Hareedy, Louise Harkness, Claudia Leemereise, Kjersten Offenbecker, Christina Donatti, Darin B Brimhall, Christian Schwabe, Craig Boyle, Michael A Hassman, Steve Knowles, Ronald D'Amico, William R Spreen","doi":"10.1002/cpdd.1538","DOIUrl":"https://doi.org/10.1002/cpdd.1538","url":null,"abstract":"Long-acting (LA) cabotegravir 200-mg/mL (CAB200) injections are approved for HIV-1 prevention and as a complete LA HIV-1 treatment regimen with rilpivirine. A high-concentration suspension formulation, cabotegravir 400 mg/mL (CAB400-D), was developed to enable less frequent dosing and self-administration. This phase 1, double-blind, randomized study (NCT04484337) evaluated intramuscular (IM) gluteal, subcutaneous (SC) abdominal, and IM thigh CAB400-D injections (200-800 mg [0.5-2.0 mL]) in adults without HIV, using CAB200 injections as active control. Co-administration with recombinant human hyaluronidase (rHuPH20), topical nonsteroidal anti-inflammatory drug, or topical steroid was evaluated for some SC injections. Pharmacokinetics, adverse events (AEs), and participant-reported outcomes were assessed. Overall, 138 participants were enrolled. Absorption was faster with CAB400-D versus CAB200. Within 4 weeks, CAB400-D plasma exposures were similar across administration routes and higher than those of CAB200. Co-administration with rHuPH20 increased the spontaneous absorption rate of CAB400-D but not CAB200. No deaths or drug-related serious AEs were observed. Five (4%) participants discontinued treatment due to AEs (injection-site reactions [ISRs], n = 3 discontinuations). Most (99%) participants experienced ≥ 1 ISR. Participants reported good acceptability of injections. Although CAB400-D injections demonstrated acceptable safety/tolerability, faster absorption than CAB200 limited potential dosing intervals to monthly dosing. Alternative cabotegravir formulations with longer dosing intervals are under clinical evaluation.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985803","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}

引用次数: 0

Bioequivalence and Tolerability of 2 Lurasidone Formulations: A Randomized, Single-Dose, 2-Period, Crossover Study in Healthy Chinese Subjects Under Fasting and Fed Conditions. 两种鲁拉西酮制剂的生物等效性和耐受性：一项随机、单剂量、2期、交叉研究，在空腹和进食条件下进行。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-04-28 DOI: 10.1002/cpdd.1529

Hengyi Yu, Yinian Fang, Xingxing Qi, Pan Luo, Zheng He, Kaifu Wang, Yongfang Lei, Donglin Zhang, Qin Zuo, Chang Liu, Qian Chen, Dong Liu, Xiuhua Ren

{"title":"Bioequivalence and Tolerability of 2 Lurasidone Formulations: A Randomized, Single-Dose, 2-Period, Crossover Study in Healthy Chinese Subjects Under Fasting and Fed Conditions.","authors":"Hengyi Yu, Yinian Fang, Xingxing Qi, Pan Luo, Zheng He, Kaifu Wang, Yongfang Lei, Donglin Zhang, Qin Zuo, Chang Liu, Qian Chen, Dong Liu, Xiuhua Ren","doi":"10.1002/cpdd.1529","DOIUrl":"https://doi.org/10.1002/cpdd.1529","url":null,"abstract":"Lurasidone is utilized in the treatment of schizophrenia and bipolar depression in adults and adolescents. In this work, a randomized, single-dose, 2-period crossover study was designed and conducted to evaluate the bioequivalence and safety of 2 lurasidone tablets. A total of 111 healthy Chinese subjects received a single dose of 40 mg lurasidone test (T) or reference (R) tablets under fasting or fed conditions, with a 7-day washout period. Blood samples were collected and lurasidone plasma concentration was quantified by liquid chromatography-tandem mass spectrometry. The pharmacokinetic properties were determined by a non-compartmental analysis, and Cmax, AUC0-t, and AUC0-inf were used for bioequivalence evaluation. As a result, the 90% confidence intervals of the geometric mean ratios between T and R fell within 80%-125% whether under fasting or fed conditions, indicating that the 2 lurasidone formulations were bioequivalent. Meanwhile, the Cmax and AUC of both T and R were approximately 2-3 times higher in the fed state compared to the fasting state. In addition, all adverse events (AEs) were classified into grade 1, and no serious or new AEs were reported. Additionally, a shorter t1/2 of the reference tablet was observed in this study compared to that of the other bioequivalence study conducted in older healthy Chinese subjects, which should be verified in the future.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981890","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}

引用次数: 0

Pharmacokinetics and Safety of TPN171 (a PDE5 Inhibitor) in Patients With Mild or Moderate Hepatic Impairment Versus Participants With Normal Hepatic Function: A Phase I Study. TPN171 （PDE5抑制剂）在轻度或中度肝功能损害患者与正常肝功能患者中的药代动力学和安全性：一项I期研究

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-04-25 DOI: 10.1002/cpdd.1535

Jing Zhou, Hong Zhang, Yanhua Ding, Zhen Wang, Yu Wang, Jiaxiang Juan, Zhicheng Jiang, Hong Chen

{"title":"Pharmacokinetics and Safety of TPN171 (a PDE5 Inhibitor) in Patients With Mild or Moderate Hepatic Impairment Versus Participants With Normal Hepatic Function: A Phase I Study.","authors":"Jing Zhou, Hong Zhang, Yanhua Ding, Zhen Wang, Yu Wang, Jiaxiang Juan, Zhicheng Jiang, Hong Chen","doi":"10.1002/cpdd.1535","DOIUrl":"https://doi.org/10.1002/cpdd.1535","url":null,"abstract":"TPN171 is a phosphodiesterase-5 inhibitor. It is currently being developed in China to treat pulmonary arterial hypertension and erectile dysfunction (ED). This study aimed to compare the pharmacokinetics and safety of TPN171 across participants with normal hepatic function and hepatic impairment (HI). An open-label, single-dose, parallel-group study enrolled participants with normal hepatic function (group C) and mild-to-moderate HI (groups A and B). In each cohort, 8 participants completed the study. Blood samples were collected up to 72 hours after 10 mg oral TPN171 administration. The maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC0-t), and AUC extrapolated to infinite time (AUC0-∞) were compared between the groups. Cmax, AUC0-t, and AUC0-∞ were higher in groups A and B than in group C (geometric mean ratios 1.17-1.20, 1.46-1.53, and 1.45-1.54, respectively), while the elimination half-time was prolonged and clearance was reduced in the HI groups. All adverse events were not serious and no participant withdrew from this study. Considering the increase in TPN171 plasma exposure, the highest dose of 5 mg TPN171 is recommended in patients with ED having mild-to-moderate HI.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989092","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}

引用次数: 0

Bioequivalence Study of Two Empagliflozin Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions. 两种恩格列净片在空腹和空腹条件下的生物等效性研究。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-04-25 DOI: 10.1002/cpdd.1530

Yuyan Lei, Yuan Liu, Lichen Gao, Xueqiong Peng, Lulu Chen, Chao Li, Weiming Chen, Junmei Xu, Dongsheng Ouyang, Xiaohui Li

{"title":"Bioequivalence Study of Two Empagliflozin Tablets in Healthy Chinese Subjects Under Fasting and Fed Conditions.","authors":"Yuyan Lei, Yuan Liu, Lichen Gao, Xueqiong Peng, Lulu Chen, Chao Li, Weiming Chen, Junmei Xu, Dongsheng Ouyang, Xiaohui Li","doi":"10.1002/cpdd.1530","DOIUrl":"https://doi.org/10.1002/cpdd.1530","url":null,"abstract":"Empagliflozin is a highly selective sodium-glucose cotransporter 2 inhibitor and an effective medication for treating diabetes. This study aimed to assess the pharmacokinetics and bioequivalence of two 10-mg empagliflozin tablets in healthy Chinese subjects and examine food's effect on absorption. The research was conducted as a single-center, randomized, open-label, single-dose, 2-way crossover study involving 47 subjects (fasting: n = 23, fed: n = 24). Subjects received either the test or reference drug and switched to the alternative after a 7-day washout period. Blood samples were collected before administration and up to 48 hours after dosing, analyzed using validated liquid chromatography-tandem mass spectrometry techniques to determine empagliflozin levels. In both studies, all 23 subjects completed the study phases under fasting and fed conditions. In both scenarios, when comparing the test and reference formulations, the 90% confidence intervals for the geometric mean ratios of maximum plasma concentration, area under the concentration-time curve from time 0 to the last measurable concentration, and area under the concentration-time curve from time 0 to infinity fell within the bioequivalence threshold of 80%-125%, confirming their acceptability. The study found that a high-fat meal slightly reduced drug exposure and slightly accelerated absorption. No serious adverse events were observed. This research confirmed the pharmacokinetic similarity of the 2 empagliflozin formulations and demonstrated their good tolerance under fasting and fed conditions.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976312","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}

引用次数: 0

Extrapolation of Midazolam Disposition in Neonates Using Physiological-Based Pharmacokinetic/Pharmacodynamic Modeling. 使用基于生理的药代动力学/药效学模型推断咪达唑仑在新生儿中的处置。

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-04-24 DOI: 10.1002/cpdd.1531

Tangping Zhao, Zhanhui Lv, Sufeng Zhou, Lu Wang, Tongtong Li, Jinying Zhu, Feng Shao

{"title":"Extrapolation of Midazolam Disposition in Neonates Using Physiological-Based Pharmacokinetic/Pharmacodynamic Modeling.","authors":"Tangping Zhao, Zhanhui Lv, Sufeng Zhou, Lu Wang, Tongtong Li, Jinying Zhu, Feng Shao","doi":"10.1002/cpdd.1531","DOIUrl":"https://doi.org/10.1002/cpdd.1531","url":null,"abstract":"There is a shortage of data in clinical studies of neonatal populations, which often utilize extrapolation strategies and model simulation techniques to support drug development and clinical applications. This study established an adult physiological-based pharmacokinetic/pharmacodynamic (PBPK/PD) model in the modeling software and extended it to neonates using pediatric extrapolation strategies based on maturation formulas for plasma albumin and CYP3A4/5. The neonatal model was then utilized to simulate midazolam dosage regimens for sedation in newborns. Individualized validation for adults indicated that 95.1% of predicted concentration values and all area under curve (AUC) values fell within a 2-fold range. The extrapolated neonatal model showed 84.4% of predicted concentrations within 2-fold, an absolute average fold error (AAFE) valuen <2, and an average fold error (AFE) value between 0.5 and 1.5, confirming the model's adequacy. The validated neonatal PBPK/PD model indicated that virtual term neonates maintained the target plasma concentration for 25 hours with the recommended dosage (0.06 mg/kg/h, intravenous infusion 12 hours). Premature infants may require a slightly higher dose than the label's recommendation (0.03 mg/kg/h, intravenous infusion 12 hours). Our findings recommend this research strategy based on extrapolation and model simulation for drug dose prediction and optimization in the neonatal population.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969097","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}

引用次数: 0

Clinical Evaluation of Potential Interaction Between Bemnifosbuvir and Ruzasvir With an Assessment of Food Effect: Results of a Phase 1 Study in Healthy Participants. 贝尼非布韦和鲁扎韦潜在相互作用与食物效应评估的临床评价：健康参与者的1期研究结果

IF 1.5 4区医学

Clinical Pharmacology in Drug Development Pub Date : 2025-04-24 DOI: 10.1002/cpdd.1540

Xiao-Jian Zhou, Gaetano Morelli, Maureen Montrond, Shannan Lynch, Keith Pietropaolo, Bruce Belanger, Arantxa Horga, Janet Hammond

{"title":"Clinical Evaluation of Potential Interaction Between Bemnifosbuvir and Ruzasvir With an Assessment of Food Effect: Results of a Phase 1 Study in Healthy Participants.","authors":"Xiao-Jian Zhou, Gaetano Morelli, Maureen Montrond, Shannan Lynch, Keith Pietropaolo, Bruce Belanger, Arantxa Horga, Janet Hammond","doi":"10.1002/cpdd.1540","DOIUrl":"https://doi.org/10.1002/cpdd.1540","url":null,"abstract":"A combination of nucleotide hepatitis C virus (HCV) nonstructural protein (NS) 5B and 5A inhibitors is a preferred standard of care for treating chronic HCV. Bemnifosbuvir is a novel oral guanosine nucleotide prodrug with potent pan-genotypic inhibitory activity against HCV NS5B. Ruzasvir, a small-molecule NS5A inhibitor, has demonstrated improved anti-HCV activity compared with first-generation NS5A inhibitors. Clinical studies have demonstrated favorable efficacy and safety of bemnifosbuvir and ruzasvir in combination with other NS5A and NS5B inhibitors, respectively. A Phase 1 study in healthy participants was conducted to assess the drug-drug interaction potential between bemnifosbuvir and ruzasvir, as well as food effects following coadministration of both compounds. Under fasted conditions, the peak, trough, and total exposure to bemnifosbuvir and its metabolites were increased upon coadministration with ruzasvir (by a maximum of 33% vs bemnifosbuvir alone), whereas the corresponding values for ruzasvir were decreased upon coadministration with bemnifosbuvir (by a maximum of 26% vs ruzasvir alone). Food delayed peak exposure to both drugs (by up to 2 hours) while increasing their peak and total exposure by up to 63%. No serious adverse events or premature drug discontinuations were reported. Overall, the study results support further evaluation of bemnifosbuvir and ruzasvir combination therapy for treating chronic HCV.","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978584","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}

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