Nilay Thakkar, Rulan Griesel, Amy Pierce, Veronica Bainbridge, Bronagh Shepherd, Konstantinos Angelis, Andrew Tomlinson, Yash Gandhi, Darin Brimhall, Daijha Anderson, Susan Andrews, Carolina Acuipil, Cynthia McCoig, Mark Baker, Paul Benn
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In addition, in part 2, the effect of VH-280 on cytochrome P450 3A (CYP3A) activity was evaluated using midazolam as a probe substrate.</p><p><strong>Results: </strong>In total, 73 participants were included (VH-280, n = 57; placebo, n = 16). Plasma exposures for VH-280 were broadly dose-proportional, and median time to maximum observed concentration was 9.0-17.0 h for the PiB and tablet formulations. Geometric mean terminal half-life was 145.8-207.8 h (> 6 days). Compared with PiB, exposures for the tablet formulation were 45-56% lower. Concomitant administration of midazolam after single and multiple doses of VH-280 did not result in clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-280 is not anticipated to inhibit or induce CYP3A4. VH-280 was well-tolerated. Frequency of adverse events (AEs) was comparable between placebo and VH-280 groups. Adverse events related to VH-280 were primarily grade 1. There were no serious AEs, AEs leading to withdrawal from drug or study, or deaths. No trends in vital signs, electrocardiograms, or laboratory hematology parameters were observed, and there were no clinically relevant changes in chemistry parameters.</p><p><strong>Conclusions: </strong>Data from this first-time-in-human study further characterize the pharmacokinetics of VH-280 after oral administration, providing support for the development of new capsid inhibitors as part of a complete long-acting regimen for the treatment and prevention of HIV-1.</p><p><strong>Clinical trial registration: </strong>ClinicalTrials.gov, NCT05163522.</p>","PeriodicalId":13592,"journal":{"name":"Infectious Diseases and Therapy","volume":" ","pages":"1313-1326"},"PeriodicalIF":5.3000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151970/pdf/","citationCount":"0","resultStr":"{\"title\":\"Clinical Pharmacokinetics and Safety of a New HIV-1 Capsid Inhibitor, VH4004280, After Oral Administration in Adults Without HIV.\",\"authors\":\"Nilay Thakkar, Rulan Griesel, Amy Pierce, Veronica Bainbridge, Bronagh Shepherd, Konstantinos Angelis, Andrew Tomlinson, Yash Gandhi, Darin Brimhall, Daijha Anderson, Susan Andrews, Carolina Acuipil, Cynthia McCoig, Mark Baker, Paul Benn\",\"doi\":\"10.1007/s40121-025-01154-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>The pharmacokinetics, drug-drug interaction potential, and safety of a new HIV-1 capsid inhibitor, VH4004280 (VH-280), are described in this first-time-in-human study.</p><p><strong>Methods: </strong>This randomized, double-blind, placebo-controlled, phase 1 study assessed oral VH-280 in adults without HIV. 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引用次数: 0
摘要
本文首次在人体研究中描述了一种新的HIV-1衣壳抑制剂VH4004280 （VH-280）的药代动力学、药物-药物相互作用潜力和安全性。方法：这项随机、双盲、安慰剂对照的1期研究评估了未感染HIV的成人口服VH-280。在第1部分和第3部分中，VH-280分别以单次递增剂量作为瓶内粉剂（PiB）和片剂给药。在第2部分中，VH-280作为PiB制剂每天一次，连续14天多次递增剂量给药。此外，在第2部分中，以咪达唑安定为探针底物，评估了VH-280对细胞色素P450 3A （CYP3A）活性的影响。结果：共纳入73名受试者(VH-280, n = 57；安慰剂组，n = 16)。血浆暴露于VH-280大致与剂量成正比，PiB和片剂到最大观察浓度的中位时间为9.0-17.0 h。几何平均终末半衰期为145.8 ~ 207.8 h （bbb6天）。与PiB相比，片剂配方的暴露量降低了45-56%。单次和多次给药VH-280后同时给药咪达唑仑不会导致咪达唑仑或1-羟咪达唑仑的临床显著变化；因此，预计VH-280不会抑制或诱导CYP3A4。VH-280耐受性良好。安慰剂组和VH-280组的不良事件发生率（ae）相当。与VH-280相关的不良事件主要为1级。没有严重的不良反应，没有导致药物或研究退出或死亡的不良反应。没有观察到生命体征、心电图或实验室血液学参数的变化趋势，化学参数也没有临床相关的变化。结论：这项首次人体研究的数据进一步表征了口服给药后VH-280的药代动力学，为开发新的衣壳抑制剂作为治疗和预防HIV-1的完整长效方案的一部分提供了支持。临床试验注册：ClinicalTrials.gov, NCT05163522。
Clinical Pharmacokinetics and Safety of a New HIV-1 Capsid Inhibitor, VH4004280, After Oral Administration in Adults Without HIV.
Introduction: The pharmacokinetics, drug-drug interaction potential, and safety of a new HIV-1 capsid inhibitor, VH4004280 (VH-280), are described in this first-time-in-human study.
Methods: This randomized, double-blind, placebo-controlled, phase 1 study assessed oral VH-280 in adults without HIV. In parts 1 and 3, VH-280 was administered as powder-in-bottle (PiB) and tablet formulations, respectively, in single ascending doses. In part 2, VH-280 was administered as a PiB formulation once daily for 14 days in multiple ascending doses. In addition, in part 2, the effect of VH-280 on cytochrome P450 3A (CYP3A) activity was evaluated using midazolam as a probe substrate.
Results: In total, 73 participants were included (VH-280, n = 57; placebo, n = 16). Plasma exposures for VH-280 were broadly dose-proportional, and median time to maximum observed concentration was 9.0-17.0 h for the PiB and tablet formulations. Geometric mean terminal half-life was 145.8-207.8 h (> 6 days). Compared with PiB, exposures for the tablet formulation were 45-56% lower. Concomitant administration of midazolam after single and multiple doses of VH-280 did not result in clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-280 is not anticipated to inhibit or induce CYP3A4. VH-280 was well-tolerated. Frequency of adverse events (AEs) was comparable between placebo and VH-280 groups. Adverse events related to VH-280 were primarily grade 1. There were no serious AEs, AEs leading to withdrawal from drug or study, or deaths. No trends in vital signs, electrocardiograms, or laboratory hematology parameters were observed, and there were no clinically relevant changes in chemistry parameters.
Conclusions: Data from this first-time-in-human study further characterize the pharmacokinetics of VH-280 after oral administration, providing support for the development of new capsid inhibitors as part of a complete long-acting regimen for the treatment and prevention of HIV-1.
期刊介绍：
Infectious Diseases and Therapy is an international, open access, peer-reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of infectious disease therapies and interventions, including vaccines and devices. Studies relating to diagnostic products and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged.
Areas of focus include, but are not limited to, bacterial and fungal infections, viral infections (including HIV/AIDS and hepatitis), parasitological diseases, tuberculosis and other mycobacterial diseases, vaccinations and other interventions, and drug-resistance, chronic infections, epidemiology and tropical, emergent, pediatric, dermal and sexually-transmitted diseases.
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