Objectives We conducted a detailed pharmacokinetic assessment in macaques treated with vaginal gels formulated with HIV integrase strand transfer inhibitors (INSTIs) to better understand drug distribution and identify INSTI concentrations associated with previously demonstrated in vivo protection against vaginal simian HIV challenge. Methods Six macaques received vaginal gel containing 1% raltegravir (30 mg) once-weekly over 6 weeks. Following a washout period, five macaques received once-weekly gel containing 0.23% L-870,812 (7 mg). Drug concentrations were measured in plasma, mucosal fluids and vaginal tissues at baseline and 2, 5 and 24 h post-dosing. Results The median maximum concentration (Cmax) for raltegravir and L-870,812 in plasma was below the limit of quantification and 41.1 ng/mL, respectively. The Cmax in vaginal fluids (1441 and 1250 μg/mL) and tissues (266.7 and 368.4 μg/g) was achieved 2–5 h after dosing, respectively. A similar half-life was observed for raltegravir and L-870,812 in vaginal fluids (8–10 h) and remained 3–4 orders of magnitude above the protein-adjusted IC95 (0.016 and 0.106 μg/mL, respectively) at 24 h. Drug concentrations in vaginal fluids correlated well with those in vaginal tissues (Pearson r ≥ 0.788). Both drugs were consistently detected in rectal fluids 2 h after vaginal dosing, albeit at much lower levels (31–92-fold) than those in vaginal fluids. Conclusions To the best of our knowledge, this study provides the first data on INSTI levels in vaginal tissues associated with in vivo protection and demonstrates rectal drug distribution of INSTIs after vaginal dosing. These findings may inform dose selection for topical products with INSTIs for HIV prevention.

中文翻译：

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猕猴阴道应用整合酶抑制剂的药代动力学

目的 我们对使用 HIV 整合酶链转移抑制剂 (INSTI) 配制的阴道凝胶治疗的猕猴进行了详细的药代动力学评估，以更好地了解药物分布并确定与先前证明的针对阴道猴 HIV 攻击的体内保护相关的 INSTI 浓度。方法 6 只猕猴每周接受一次含有 1% raltegravir (30 mg) 的阴道凝胶，为期 6 周。在冲洗期之后，五只猕猴每周接受一次含有 0.23% L-870,812 (7 mg) 的凝胶。在基线和给药后 2、5 和 24 小时测量血浆、粘膜液和阴道组织中的药物浓度。结果 raltegravir 和 L-870,812 在血浆中的中位最大浓度 (Cmax) 分别低于定量限和 41.1 ng/mL。给药后 2-5 小时分别达到阴道液（1441 和 1250 μg/mL）和组织（266.7 和 368.4 μg/g）中的 Cmax。在阴道液（8-10 小时）中观察到 raltegravir 和 L-870,812 的半衰期相似，并且在 24 小时时保持比蛋白质调整的 IC95（分别为 0.016 和 0.106 μg/mL）高 3-4 个数量级。阴道液中的药物浓度与阴道组织中的药物浓度密切相关（Pearson r ≥ 0.788）。两种药物在阴道给药后 2 小时均在直肠液中检测到，尽管水平比阴道液中的水平低得多（31-92 倍）。结论 据我们所知，本研究首次提供了与体内保护相关的阴道组织中 INSTI 水平的数据，并证明了阴道给药后 INSTI 的直肠药物分布。