Margolis David, Watkins Michael, Zhu Yali
Brii Biosciences Inc., Durham, North Carolina, USA.
Antimicrob Agents Chemother. 2025 Jun 4;69(6):e0020025. doi: 10.1128/aac.00200-25. Epub 2025 Apr 22.
BRII-732, a medoxomil carbonate prodrug of EFdA, is designed for once weekly dosing as part of combination antiretroviral therapy for HIV. Two single-center, randomized, double-blind, placebo-controlled phase 1 studies evaluated its safety, tolerability, and pharmacokinetics in 72 healthy adult participants. Study 1 assessed single doses (10-200 mg) and multiple weekly doses (10, 25 mg), while Study 2 investigated lower doses (≤2.5 mg) and relative bioavailability of tablet versus oral solution. In Study 1, the first single-dose cohort and the first multiple-dose cohort each enrolled four participants (three active; one placebo); the remaining cohorts each enrolled eight participants (six active; two placebo). In Study 2, each cohort enrolled eight participants (six active; two placebo). BRII-732 was well tolerated, with most TEAEs being mild and no SAEs, or withdrawals. Clinical laboratory tests, vital signs, and ECGs revealed no significant abnormalities. Plasma BRII-732 concentrations were largely below the limit of quantification, confirming efficient conversion to EFdA. Plasma exposures of EFdA increased near dose-proportionality, with a mean of 1.50-2.94 hours (≤10 mg) and 55-112 hours (25-200 mg). EFdA showed no accumulation in plasma after weekly dosing. Intracellularly, EFdA-TP demonstrated rapid formation, slow elimination (: 194-227 hours), and meaningful accumulation after weekly dosing, with an estimated steady-state accumulation ratio of ~2.2-2.5. Tablet and solution formulations exhibited comparable systemic exposure. These studies highlight the favorable safety, tolerability, and pharmacokinetic profile of once weekly BRII-732 in healthy adult participants.
BRII-732是替诺福韦艾拉酚胺（EFdA）的碳酸亚甲绿酯前药，设计用于每周给药一次，作为HIV联合抗逆转录病毒治疗的一部分。两项单中心、随机、双盲、安慰剂对照的1期研究评估了其在72名健康成年参与者中的安全性、耐受性和药代动力学。研究1评估了单次剂量（10 - 200毫克）和每周多次剂量（10、25毫克），而研究2研究了较低剂量（≤2.5毫克）以及片剂与口服溶液的相对生物利用度。在研究1中，第一个单剂量队列和第一个多剂量队列各招募了4名参与者（3名活性药物组；1名安慰剂组）；其余队列各招募了8名参与者（6名活性药物组；2名安慰剂组）。在研究2中，每个队列招募了8名参与者（6名活性药物组；2名安慰剂组）。BRII-732耐受性良好，大多数治疗中出现的不良事件为轻度，无严重不良事件或停药情况。临床实验室检查、生命体征和心电图均未发现明显异常。血浆BRII-732浓度大多低于定量限，证实其有效转化为EFdA。EFdA的血浆暴露量接近剂量比例增加，平均消除半衰期为1.50 - 2.94小时（≤10毫克）和55 - 112小时（25 - 200毫克）。每周给药后，EFdA在血浆中未显示出蓄积。在细胞内，EFdA-TP显示出快速形成、缓慢消除（消除半衰期：194 - 227小时），且每周给药后有明显蓄积现象，估计稳态蓄积比约为2.2 - 2.5。片剂和溶液制剂表现出相当的全身暴露。这些研究突出了每周一次的BRII-732在健康成年参与者中良好的安全性、耐受性和药代动力学特征。
