Clinical Pharmacology in Drug Development最新文献

{"title":"Safety, Tolerability, and Pharmacokinetics of Donanemab in Healthy Chinese Participants: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study","authors":"Junyu Xu,&nbsp;Nan Zhao,&nbsp;Yihui Wang,&nbsp;Ivelina Gueorguieva,&nbsp;Chenxi Qian,&nbsp;Yimin Cui","doi":"10.1002/cpdd.1533","DOIUrl":"10.1002/cpdd.1533","url":null,"abstract":"<p>Alzheimer's disease (AD), characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles, is the leading cause of dementia globally. Donanemab is a humanized immunoglobulin G1 in development as a treatment to slow AD progression. This study aimed to evaluate the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of donanemab in healthy Chinese adults. The study included screening, inpatient, and follow-up periods. Following successful screening, participants were assigned to one of three donanemab cohorts (350, 700, or 1400 mg) and randomized in a 5:1 ratio to receive donanemab or placebo. Participants received a single intravenous (IV) dose of donanemab or placebo, and the safety, PKs, and immunogenicity of donanemab were monitored. A total of 36 male Chinese participants were included. All treatment-emergent adverse events (TEAEs) were mild in severity. Two participants on 350 mg donanemab experienced treatment-related TEAEs. Serum concentrations decreased over time with dose-dependent PK parameters (C_max, t_1/2, AUC_0-tlast, and AUC_0-inf) as expected. Clearance values were similar across doses. All donanemab recipients developed treatment-emergent antidrug antibodies (ADAs) in the inpatient and follow-up periods, with similar ADA titer ranges across all donanemab doses. Single IV doses of donanemab 350, 700, and 1400 mg showed acceptable safety, tolerability, and dose-proportional PK in healthy Chinese adults.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"598-604"},"PeriodicalIF":1.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1533","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076447","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":"Evaluation of Potential Effects of CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Fruquintinib in Healthy Subjects","authors":"Martha Gonzalez,&nbsp;Zhao Yang,&nbsp;William R Schelman,&nbsp;Xiaofei Zhou,&nbsp;Neeraj Gupta,&nbsp;Caly Chien","doi":"10.1002/cpdd.1520","DOIUrl":"10.1002/cpdd.1520","url":null,"abstract":"<p>Cytochrome P450 (CYP) 3A plays a significant role in fruquintinib metabolism in vitro. This 2-part, 2-period fixed-sequence study investigated the impact of CYP3A inhibition (itraconazole) and CYP3A induction (rifampin) on the pharmacokinetics (PK) of fruquintinib and M11, its main metabolite. Fourteen healthy subjects in each part received a single dose of fruquintinib 5 mg alone in Period 1 and with itraconazole (Part A) or rifampin (Part B) in Period 2 under fasted conditions. Itraconazole or rifampin was administered daily 4 or 7 days before coadministration, respectively; administration of both continued throughout the PK sampling period. PK samples were collected before dosing and over 168 hours after fruquintinib dosing. Coadministration with itraconazole resulted in an increase of fruquintinib systemic exposure, determined by area under the plasma concentration-time curves (AUCs) by approximately 10%. Decreases in M11 AUCs and maximum plasma concentration (C_max) ranged from 44% to 55% but were not considered clinically meaningful. Rifampin reduced fruquintinib C_max and AUCs by 12% and 65%, respectively. Rifampin had a marginal effect on M11 AUCs and increased M11 C_max by 2.3-fold. Data support that concomitant use of fruquintinib with potent CYP3A inducers of rifampin-like potency should be avoided, but no dose adjustment is recommended when coadministered with CYP3A inhibitors.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"605-613"},"PeriodicalIF":1.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955741","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":"Pharmacokinetics and Safety Evaluation of a New Generic Sitafloxacin: A Phase I Bioequivalence Study in Healthy Chinese Participants","authors":"Yongfang Lei,&nbsp;Pan Luo,&nbsp;Yuzhu Chen,&nbsp;Liuliang Xue,&nbsp;Donglin Zhang,&nbsp;Xingxing Qi,&nbsp;Yinian Fang,&nbsp;Hengyi Yu,&nbsp;Zheng He,&nbsp;Qin Zuo,&nbsp;Chang Liu,&nbsp;Dong Liu,&nbsp;Xinhua Ren,&nbsp;Qian Chen","doi":"10.1002/cpdd.1519","DOIUrl":"10.1002/cpdd.1519","url":null,"abstract":"<p>Sitafloxacin is a new antibiotic drug belonging to the fourth generation quinolone antibiotics. The aim of this study was to evaluate the pharmacokinetics (PK), safety profiles, and bioequivalence of test and reference 50-mg sitafloxacin tablets under fasting and fed conditions. The PK parameters, which were calculated with noncompartmental model, including maximum concentration, area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration, and AUC from time 0 to infinity. The bioequivalence was assessed on the basis of whether the 90% confidence intervals of the geometric mean ratio for the test/reference drugs fell within the accepted range of 80%-125%. Adverse events were monitored to assess safety. Finally, 80 healthy Chinese participants were enrolled, of which 40 were enrolled in the fasting study and the other 40 enrolled in the fed study. There was 1 participant in the fed trial who withdrew from the study because of failure to finish the high-fat meal. The geometric mean ratio and its 90% confidence interval for the maximum concentration, AUC from time 0 to the last quantifiable concentration, AUC from time 0 to infinity between the branded and generic sitafloxacin, under both fasting and fed conditions, were compliant with the predefined bioequivalence criteria of 80%-125%. No serious adverse events were observed in this study. Therefore, the findings indicate that generic and original sitafloxacin tablets have comparable bioequivalence and safety profiles.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"592-597"},"PeriodicalIF":1.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995720","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":"Effect of Mild to Moderate Hepatic Impairment on Valemetostat Pharmacokinetics: An Open-Label, Phase I Study","authors":"Masaya Tachibana,&nbsp;Thuy Vu Craveiro,&nbsp;Thomas C. Marbury,&nbsp;Samuel Oberstein,&nbsp;George J. Atiee,&nbsp;Ben Tao,&nbsp;Takako Shimizu,&nbsp;Yvonne Lau,&nbsp;Malaz A. Abutarif","doi":"10.1002/cpdd.1544","DOIUrl":"10.1002/cpdd.1544","url":null,"abstract":"<p>Valemetostat tosylate (valemetostat) is a dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1, approved in Japan for the treatment of relapsed/refractory peripheral T-cell lymphoma and adult T-cell leukemia/lymphoma. This Phase I, open-label study evaluated the pharmacokinetics and safety of a single 50-mg oral dose of valemetostat in participants with hepatic impairment (HI). In total, 24 participants were enrolled into 3 cohorts of mild HI (n = 8) and moderate HI (n = 8) according to the National Cancer Institute's Organ Dysfunction Working Group criteria, and matched healthy participants with normal hepatic function (HF; n = 8). In participants with mild and moderate HI, total valemetostat (bound + unbound) area under the concentration-time curve extrapolated to infinity was 23% lower (geometric mean ratio [GMR], 77.2% [90% confidence interval (CI), 44.0-135]) and 35% lower, (GMR, 64.8% [90% CI, 40.6-103]), respectively, and unbound valemetostat was 19% lower (GMR, 81.1% [90% CI, 47.4-139]) and 15% higher (GMR, 115% [90% CI, 75.5-176]), than in participants with normal HF. No treatment-related adverse events were reported. Based on the result of this trial, no dosing adjustments are recommended for patients with mild to moderate HI receiving valemetostat.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 8","pages":"631-641"},"PeriodicalIF":1.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982842","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":"Pharmacokinetic and Bioequivalence Evaluation of Prolonged-Release Octreotide Acetate Microspheres in Healthy Human Subjects","authors":"Chenjing Wang,&nbsp;Xin Li,&nbsp;Xingli Gu,&nbsp;Haixun Hu,&nbsp;Zhaoguo Lv,&nbsp;Yanhua Sun,&nbsp;Yanzhi Li,&nbsp;Chenxi Hao,&nbsp;Yanping Liu,&nbsp;Yao Fu,&nbsp;Qingmin Yang,&nbsp;Yu Cao","doi":"10.1002/cpdd.1521","DOIUrl":"10.1002/cpdd.1521","url":null,"abstract":"<p>Somatostatin analogs such as octreotide have been used in the treatment of acromegaly in the past decades, due to their efficacy in relieving symptoms and lowering growth hormone and insulin-like growth factor 1 levels. Herein, the pharmacokinetic (PK) profile and safety of generic (test product) octreotide acetate microspheres and brand name (reference product) octreotide acetate microspheres in healthy volunteers were compared to assess the bioequivalence. Healthy volunteers were randomized 1:1 to receive single doses of the test product and reference product, respectively. Blood samples of each patient were collected at specific time intervals over an 82-day period. Plasma drug concentrations were tested. The PK parameters were analyzed and compared. Analysis of variance on log-transformed primary PK parameters was applied to analyze the bioequivalence between the test and reference product. The bioequivalence margin was 80%-125%. The PK parameters between the 2 groups were numerically similar. All 90% confidence intervals of the geometric mean ratio for the primary PK parameters fell within 80%-125%, confirming the bioequivalence of the 2 drugs. In this study, 172 (73.9%) adverse events, including 1 (0.4%) non-treatment-related serious adverse event in the test group, were reported. The test product is bioequivalent to the reference product with acceptable safety. The octreotide acetate microspheres provided by 2 sponsors are alternative products.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 7","pages":"505-510"},"PeriodicalIF":1.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981537","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 2-Part, Open-Label, Phase 1 Bioequivalence and Food-Effect Study of Ubrogepant in Healthy Adult Participants","authors":"Ramesh Boinpally,&nbsp;Joel M. Trugman","doi":"10.1002/cpdd.1546","DOIUrl":"10.1002/cpdd.1546","url":null,"abstract":"<p>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 (<i>n</i>  =  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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 7","pages":"511-519"},"PeriodicalIF":1.8,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1546","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Cytochrome P450 3A Inhibition and Induction by Itraconazole and Rifampin on Tazemetostat Pharmacokinetics in Patients With Advanced Malignancies","authors":"Yingxue Chen,&nbsp;Renli Teng,&nbsp;Attila Szanto,&nbsp;Apoorva Kapopara,&nbsp;Rajat Bannerji,&nbsp;Julien Ogier,&nbsp;Devalingam Mahalingam","doi":"10.1002/cpdd.1543","DOIUrl":"10.1002/cpdd.1543","url":null,"abstract":"<p>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 (C_max) and area under the concentration-time curve from time 0 to 12 hours (AUC_0-12h) by 2.00- and 3.12-fold, respectively, after single doses. Following twice-daily dosing, itraconazole increased mean steady-state C_max and AUC_0-12h by 1.86- and 2.47-fold, respectively. Rifampin coadministration decreased tazemetostat steady-state (C_max) and AUC_0-12h 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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 7","pages":"520-527"},"PeriodicalIF":1.8,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1543","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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,&nbsp;Yuan Liu,&nbsp;Hongcheng Li,&nbsp;Yuyan Lei,&nbsp;Fangliang Gan,&nbsp;Yusi Wu,&nbsp;Xiaohui Li,&nbsp;Yusheng Zhou","doi":"10.1002/cpdd.1537","DOIUrl":"10.1002/cpdd.1537","url":null,"abstract":"<p>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 (C_max) of the drug when comparing the 2 SMZ/TMP formulations. Furthermore, the 90% confidence intervals for the ratios of the geometric means of C_max, the area under the curve from 0 time to the last quantifiable concentration point (AUC_0-t), and the area under the curve extrapolated to an infinite time point (AUC_0-∞) 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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 7","pages":"557-564"},"PeriodicalIF":1.8,"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}

{"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,&nbsp;Alexandra Cole,&nbsp;Viviana Bozón,&nbsp;Erika Manyak,&nbsp;Jonathan Novak,&nbsp;Barbara Yang,&nbsp;Briohny A. Johnston,&nbsp;Sudha Parasuraman,&nbsp;Kushal J. Paneliya,&nbsp;Virna Schuck","doi":"10.1002/cpdd.1539","DOIUrl":"10.1002/cpdd.1539","url":null,"abstract":"<p>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 C_max and AUC_inf increased with dose, and T_max was 2 hours. RBN-3143 was cleared from plasma with an apparent terminal half-life ranging from 3 to 11 hours. In the MAD, C_max and AUC_inf 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 C_max and AUC_inf 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 C_max and AUC_inf ratios of 0.92 and 0.88, respectively. The clinical pharmacology properties of RBN-3143 in HVs support further development for inflammatory diseases.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 7","pages":"493-504"},"PeriodicalIF":1.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1539","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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,&nbsp;Paul Benn,&nbsp;Jörg Sievers,&nbsp;David Dorey,&nbsp;Michael Warwick-Sanders,&nbsp;Randa Hareedy,&nbsp;Louise Harkness,&nbsp;Claudia Leemereise,&nbsp;Kjersten Offenbecker,&nbsp;Christina Donatti,&nbsp;Darin B. Brimhall,&nbsp;Christian Schwabe,&nbsp;Craig Boyle,&nbsp;Michael A. Hassman,&nbsp;Steve Knowles,&nbsp;Ronald D'Amico,&nbsp;William R. Spreen","doi":"10.1002/cpdd.1538","DOIUrl":"10.1002/cpdd.1538","url":null,"abstract":"<p>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.</p>","PeriodicalId":10495,"journal":{"name":"Clinical Pharmacology in Drug Development","volume":"14 7","pages":"528-541"},"PeriodicalIF":1.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpdd.1538","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}