Clinical Pharmacokinetics and Safety of Orally Administered VH4011499, a New HIV-1 Capsid Inhibitor, in Adults Without HIV.

IF 4.7 3区医学 Q1 INFECTIOUS DISEASES

Infectious Diseases and Therapy Pub Date : 2025-05-01 Epub Date: 2025-04-02 DOI:10.1007/s40121-025-01129-y

Nilay Thakkar, Rulan Griesel, Amy Pierce, Veronica Bainbridge, Bronagh Shepherd, Konstantinos Angelis, Andrew Tomlinson, Yash Gandhi, Darin Brimhall, Brian Spears, Daijha Anderson, Emma Pinnick, Carolina Acuipil, Cynthia McCoig, Mark Baker, Paul Benn

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引用次数: 0

Abstract

Introduction: This first-time-in-human study describes the pharmacokinetics, drug-drug interaction potential, and safety of VH4011499 (VH-499), a new HIV-1 capsid inhibitor.

Methods: This double-blind, randomized, placebo-controlled, phase 1 study evaluated VH-499 in adults without HIV administered orally as single ascending doses as powder-in-bottle (PiB; part 1) and tablet (part 3) formulations and as multiple ascending doses as PiB formulation dosed once daily for 14 days (part 2). Midazolam was used to evaluate the effect of VH-499 on cytochrome P450 3A (CYP3A) activity (part 2).

Results: Overall, 73 participants were included (VH-499, n = 56; placebo, n = 17). VH-499 plasma exposures were less than dose-proportional, with median time to maximum observed concentration of 8.0-12.0 h for the PiB formulation and 24.0 h for the tablet formulation. Geometric mean terminal half-life was 51.2-66.5 h (2-3 days). The tablet formulation resulted in 45-63% lower exposures compared with PiB. Concomitant midazolam administration after single and multiple VH-499 doses did not lead to clinically significant changes in midazolam or 1-hydroxymidazolam exposures; therefore, VH-499 is not expected to inhibit or induce CYP3A4. VH-499 was well tolerated. Adverse event (AE) frequency was comparable between placebo and VH-499 groups. VH-499-related AEs were predominantly grade 1. No serious AEs across VH-499 groups, AEs leading to withdrawal from drug/study, or deaths occurred. There were no trends in vital signs, electrocardiograms, or laboratory hematology parameters and no clinically relevant changes in chemistry parameters.

Conclusion: First-time-in-human data further characterize the pharmacokinetics of orally administered VH-499 and provide support for development of VH-499 as part of a complete long-acting regimen for HIV-1 treatment and prevention.

Clinical trial registration: ClinicalTrials.gov, NCT05393271.

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口服新型HIV-1衣壳抑制剂VH4011499在无HIV成人中的临床药代动力学和安全性

这项首次人体研究描述了一种新的HIV-1衣壳抑制剂VH4011499 （VH-499）的药代动力学、药物-药物相互作用潜力和安全性。方法：这项双盲、随机、安慰剂对照的1期研究评估了VH-499在未感染艾滋病毒的成人中以单次递增剂量口服，如瓶内粉剂(PiB；（第1部分）和片剂（第3部分）制剂，以及多次递增剂量的PiB制剂，每天给药一次，持续14天（第2部分）。咪达唑仑用于评估VH-499对细胞色素P450 3A （CYP3A）活性的影响（第2部分）。结果：总体而言，包括73名参与者(VH-499, n = 56；安慰剂组，n = 17)。VH-499血浆暴露低于剂量正比，PiB制剂达到最大观察浓度的中位时间为8.0-12.0 h，片剂制剂为24.0 h。几何平均终末半衰期为51.2 ~ 66.5 h（2 ~ 3天）。与PiB相比，片剂配方的暴露率降低了45-63%。VH-499单次和多次给药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-499不会抑制或诱导CYP3A4。VH-499耐受性良好。不良事件（AE）频率在安慰剂组和VH-499组之间具有可比性。vh -499相关ae主要为1级。VH-499组未发生严重不良反应，未发生导致退出药物/研究或死亡的不良反应。生命体征、心电图或实验室血液学参数无变化趋势，化学参数无临床相关变化。结论：首次人体数据进一步表征了口服VH-499的药代动力学特征，并为开发VH-499作为HIV-1治疗和预防的完整长效方案的一部分提供了支持。临床试验注册：ClinicalTrials.gov, NCT05393271。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Infectious Diseases and Therapy Medicine-Microbiology (medical)

CiteScore

8.60

自引率

1.90%

发文量

136

审稿时长

6 weeks

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.