Thakkar Nilay, Griesel Rulan, Pierce Amy, Bainbridge Veronica, Shepherd Bronagh, Angelis Konstantinos, Tomlinson Andrew, Gandhi Yash, Brimhall Darin, Anderson Daijha, Andrews Susan, Acuipil Carolina, McCoig Cynthia, Baker Mark, Benn Paul
GSK, 1250 S Collegeville Road, Collegeville, PA, 19426, USA.
ViiV Healthcare, 79 New Oxford Street, London, WC1A 1DG, UK.
Infect Dis Ther. 2025 Jun;14(6):1313-1326. doi: 10.1007/s40121-025-01154-x. Epub 2025 Apr 26.
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.
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.
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.
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.
ClinicalTrials.gov, NCT05163522.
在这项首次人体研究中，描述了新型HIV-1衣壳抑制剂VH4004280（VH-280）的药代动力学、药物相互作用潜力和安全性。
这项随机、双盲、安慰剂对照的1期研究评估了无HIV的成年人口服VH-280的情况。在第1部分和第3部分中，VH-280分别以瓶内粉剂（PiB）和片剂剂型，单剂量递增给药。在第2部分中，VH-280以PiB剂型每日给药1次，共14天，多剂量递增给药。此外，在第2部分中，使用咪达唑仑作为探针底物评估VH-280对细胞色素P450 3A（CYP3A）活性的影响。
总共纳入了73名参与者（VH-280组，n = 57；安慰剂组，n = 16）。VH-280的血浆暴露量与剂量大致成比例，PiB和片剂剂型达到最大观察浓度的中位时间为9.0 - 17.0小时。几何平均末端半衰期为145.8 - 207.8小时（> 6天）。与PiB相比，片剂剂型的暴露量低45 - 56%。单剂量和多剂量VH-280后同时给予咪达唑仑，咪达唑仑或1-羟基咪达唑仑的暴露量没有出现具有临床意义的变化；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（AE）发生率相当。与VH-280相关的不良事件主要为1级。没有严重不良事件、导致停药或退出研究的不良事件或死亡。未观察到生命体征、心电图或实验室血液学参数的趋势，化学参数也没有临床相关变化。
这项首次人体研究的数据进一步描述了口服VH-280后的药代动力学特征，为开发新型衣壳抑制剂作为完整长效HIV-1治疗和预防方案的一部分提供了支持。
ClinicalTrials.gov，NCT05163522。
