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一种HIV广泛中和单克隆抗体VRC07-523LS的药代动力学相互作用评估:对三项针对未感染HIV人群的1期试验的跨方案分析

Pharmacokinetic interaction assessment of an HIV broadly neutralizing monoclonal antibody VRC07-523LS: a cross-protocol analysis of three phase 1 trials in people without HIV.

作者信息

Chawana Tariro D, Walsh Stephen R, Stranix-Chibanda Lynda, Chirenje Zvavahera M, Yu Chenchen, Zhang Lily, Seaton Kelly E, Heptinstall Jack, Zhang Lu, Paez Carmen A, Gamble Theresa, Karuna Shelly T, Andrew Philip, Hanscom Brett, Sobieszczyk Magdalena E, Edupuganti Srilatha, Gay Cynthia L, Mannheimer Sharon B, Hurt Christopher B, Stephenson Kathryn E, Polakowski Laura L, Spiegel Hans, Yacovone Margaret, Regenold Stephanie, Yen Catherine, Baumblatt Jane Ag, Gama Lucio, Barouch Dan H, Piwowar-Manning Estelle, Koup Richard A, Tomaras Georgia D, Hyrien Ollivier, Roxby Alison C, Huang Yunda

机构信息

University of Zimbabwe Clinical Trials Research Centre (UZ-CTRC), Harare, Zimbabwe.

Harvard Medical School, Boston, MA, USA.

出版信息

BMC Immunol. 2025 Feb 19;26(1):8. doi: 10.1186/s12865-025-00687-7.

Abstract

VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed. We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (n = 95) or subcutaneous (n = 51) VRC07-523LS, either alone ('single'; n = 100) or in combination with 1 or 2 other mAbs ('combined'; n = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities. We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups. These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention.

摘要

VRC07-523LS是一种靶向HIV包膜(Env)三聚体上CD4结合位点的安全且耐受性良好的单克隆抗体(mAb)。VRC07-523LS与靶向其他HIV表位的单克隆抗体联合使用的疗效将在即将开展的试验中进行评估,以预防成人感染HIV。然而,单独给药与与其他单克隆抗体联合给药时VRC07-523LS的药代动力学(PK)差异尚未得到正式评估。我们对三项临床试验进行了跨方案分析,纳入了总共146名未感染HIV的成年人的数据,这些人接受了静脉注射(n = 95)或皮下注射(n = 51)的VRC07-523LS,单独使用(“单一用药”;n = 100)或与1种或2种其他单克隆抗体联合使用(“联合用药”;n = 46)。我们使用开放的二室群体PK模型来描述VRC07-523LS随时间变化的血清浓度,并考虑个体间变异性。我们使用目标最大似然估计方法比较联合用药组与单一用药组之间的个体水平PK参数,以调整参与者特征。在清除率、房室间清除率、分布半衰期或随时间变化的VRC07-523LS总暴露量方面未观察到显著差异。然而,联合用药组的平均中央分布容积、外周分布容积和消除半衰期略大,这对应于给药后早期预测浓度略低,而两组均维持较高水平。这些结果表明VRC07-523LS与其他单克隆抗体之间可能存在PK相互作用,但在HIV预防背景下临床影响较小。我们的研究结果支持VRC07-523LS与其他单克隆抗体联合给药,并使用所建立的PK模型来设计未来的HIV预防试验。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eb3/11837431/3c08582609dc/12865_2025_687_Fig1_HTML.jpg

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