A lubricating microbicide gel designed for rectal and vaginal use would provide a behaviorally congruent strategy to enhance pre-exposure prophylaxis adherence and reduce HIV infection risk. In this study, we report the first-in-human evaluation of such a gel containing 1% IQP-0528, an investigational antiretroviral. Seven HIV-1-negative participants received one 10 mL rectal dose of radiolabeled 1% IQP-0528 gel. We assessed safety; IQP-0528 pharmacokinetics in plasma, and rectal and vaginal tissue; ex vivo local pharmacodynamics (PD); and colorectal distribution. The 1% gel was determined to be safe with one mild event attributed to study product and no effects on rectal tissue histology. All concentrations measured in plasma and vaginal tissue were below the limit of quantitation. Median IQP-0528 concentrations in rectal tissue exceeded the in vitro EC₉₅ against HIV-1 (0.07 ng/mg) by 3–5 h of dosing and remained above this concentration for at least 24 h, despite a 3-log reduction in concentration over this duration of time. Rectal tissue PD—assessed by ex vivo HIV challenge—demonstrated significant p24 antigen reduction 3–5 h postdose compared with baseline (p = .05), but not 24–26 h postdose (p = .75). Single-photon emission computed tomography/computed tomography imaging revealed that product distribution was localized to the rectosigmoid. The IQP-0528 gel possesses desirable features for a topical microbicide including: local safety with no systemic absorption, delivery of locally high IQP-0528 concentrations, and significant reductions in ex vivo HIV infectivity. However, the gel is limited by its rapid clearance and inability to penetrate vaginal tissues following rectal dosing.

中文翻译：

---

检查用于 HIV 暴露前预防的直肠给药 IQP-0528 凝胶的安全性、药代动力学和药效学：一项首次人体研究

设计用于直肠和阴道使用的润滑杀菌剂凝胶将提供行为一致的策略，以增强暴露前预防的依从性并降低 HIV 感染风险。在这项研究中，我们报告了对这种含有 1% IQP-0528（一种研究性抗逆转录病毒药物）的凝胶的首次人体评估。七名 HIV-1 阴性参与者接受了 10 mL 直肠剂量的放射性标记 1% IQP-0528 凝胶。我们评估了安全性；IQP-0528 在血浆、直肠和阴道组织中的药代动力学；离体局部药效学（PD）；和结肠直肠分布。1% 的凝胶被确定是安全的，其中一个轻微事件归因于研究产品，并且对直肠组织组织学没有影响。在血浆和阴道组织中测得的所有浓度均低于定量限。直肠组织中的中位 IQP-0528 浓度在给药 3-5 小时时超过了针对 HIV-1的体外EC ₉₅ (0.07 ng/mg)，并在该浓度之上保持至少 24 小时，尽管浓度降低了 3 个对数在这段时间内。直肠组织 PD——通过体外HIV 攻击评估——与基线相比，在给药后 3-5 小时显示 p24 抗原显着减少（p  = .05），但在给药后 24-26 小时则没有（p = .75)。单光子发射计算机断层扫描/计算机断层扫描成像显示产品分布位于直肠乙状结肠。IQP-0528 凝胶具有局部杀微生物剂的理想特性，包括：局部安全，无全身吸收，局部高浓度 IQP-0528 的递送，以及显着降低离体HIV 感染性。然而，凝胶受到其快速清除和直肠给药后无法穿透阴道组织的限制。