Zheng Yanan, Wire Mary, Omange Robert Were, deVries Christiaan R, Zhang Liao, Chen Buyun, Huang Susie S Y, Cruz Kimberly, Hassman Howard, Osiyemi Olayemi, Rondon Juan Carlos, Lim Daina, West Steve, Wen Anita, Wallin Jeffrey J, SenGupta Devi, Cai Yanhui
Gilead Sciences, Foster City, CA, USA.
Advanced Pharma, Miami, FL, USA.
Infect Dis Ther. 2025 Sep 15. doi: 10.1007/s40121-025-01227-x.
Vesatolimod (VES), a toll-like receptor 7 agonist, is being investigated as part of a strategy for human immunodeficiency virus (HIV) cure. VES is metabolized through the CYP3A pathway and is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). This study evaluated the impact of coadministration of VES with cobicistat (COBI; a P-gp, BCRP, and strong CYP3A inhibitor) or voriconazole (VOR; a strong CYP3A inhibitor with no effect on transporters) on the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VES in people with HIV (PWH).
A total of 15 people with virally suppressed HIV on antiretroviral therapy received 2 mg VES (on day 1 in period 1, day 2 in period 2, and day 3 in period 3), 150 mg COBI once daily for 5 days in period 2, and 400 mg VOR on day 1 and 200 mg twice daily on days 2-6 in period 3. Blood samples were collected to measure VES PK, expression of interferon-stimulated genes (ISGs), cytokine/chemokine levels, and immune-cell phenotyping.
Coadministration of VES with VOR did not impact VES PK. In contrast, coadministration of COBI increased VES maximum plasma concentration (C), area under the concentration-time curve extrapolated to infinity (AUC), and half-life (t) 7.5-, 4.3-, and 1.2-fold, respectively, but did not increase the mRNA expression levels of ISGs, serum cytokines/chemokines, or expression of activation markers on peripheral natural killer or T cells compared with VES alone. There were no serious adverse events, and no participants discontinued study drugs due to study-drug-related adverse events.
VES was well tolerated when administered alone or in combination with COBI or VOR in PWH. Coadministration of COBI, but not VOR, increased plasma VES concentrations, suggesting that inhibition of transporters (P-gp and/or BCRP) may have a greater impact on VES PK than inhibition of the drug-metabolizing enzyme (CYP3A).
ClinicalTrials.gov NCT05458102.
维沙托利莫德（VES）是一种Toll样受体7激动剂，正作为人类免疫缺陷病毒（HIV）治愈策略的一部分进行研究。VES通过CYP3A途径代谢，是外排转运蛋白P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP）的底物。本研究评估了VES与考比司他（COBI；一种P-gp、BCRP和强效CYP3A抑制剂）或伏立康唑（VOR；一种对转运蛋白无影响的强效CYP3A抑制剂）合用对HIV感染者（PWH）中VES的安全性、药代动力学（PK）和药效学（PD）的影响。
共有15名接受抗逆转录病毒治疗且病毒得到抑制的HIV感染者，在第1阶段第1天、第2阶段第2天和第3阶段第3天接受2mg VES，在第2阶段每天一次服用150mg COBI，共5天，在第3阶段第1天接受400mg VOR，第2 - 6天每天两次接受200mg VOR。采集血样以测量VES的PK、干扰素刺激基因（ISG）的表达、细胞因子/趋化因子水平以及免疫细胞表型。
VES与VOR合用不影响VES的PK。相比之下，COBI合用使VES的最大血浆浓度（C）、外推至无穷大的浓度 - 时间曲线下面积（AUC）和半衰期（t）分别增加了7.5倍、4.3倍和1.2倍，但与单独使用VES相比，未增加ISG的mRNA表达水平、血清细胞因子/趋化因子或外周自然杀伤细胞或T细胞上激活标志物的表达。没有严重不良事件，也没有参与者因与研究药物相关的不良事件而停用研究药物。
在PWH中，单独使用或与COBI或VOR联合使用时，VES耐受性良好。COBI合用增加了血浆VES浓度，而VOR合用未增加，这表明转运蛋白（P-gp和/或BCRP）的抑制对VES PK的影响可能大于药物代谢酶（CYP3A）的抑制。
ClinicalTrials.gov NCT05458102。
