School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.
Envigo, Huntingdon, Cambridgeshire, United Kingdom.
Antimicrob Agents Chemother. 2017 Sep 22;61(10). doi: 10.1128/AAC.00965-17. Print 2017 Oct.
5P12-RANTES, a chemokine analogue that potently blocks the HIV CCR5 coreceptor, is being developed as both a vaginal and rectal microbicide for prevention of sexual transmission of HIV. Here, we report the first pharmacokinetic data for 5P12-RANTES following single-dose vaginal gel administration in sheep. Aqueous gel formulations containing low (1.24-mg/ml), intermediate (6.18-mg/ml), and high (32.0-mg/ml; suspension-type gel) concentrations of 5P12-RANTES were assessed via rheology, syringeability, and release testing. Following vaginal gel administration to sheep, 5P12-RANTES concentrations were measured in vaginal fluid, vaginal tissue, and serum over a 96-h period. All gels showed non-Newtonian pseudoplastic behavior, with the high-concentration gels exhibiting a greater viscosity and cohesive structure than the intermediate- and low-concentration gels. In release testing, >90% 5P12-RANTES was released from the low- and intermediate-concentration gels after 72 h. For the high-concentration gel, ∼50% 5P12-RANTES was detected, attributed to protein denaturation during lyophilization and/or subsequent solvation of the protein within the gel matrix. In sheep, 5P12-RANTES concentrations in vaginal fluid, vaginal tissue, and serum increased in a dose-dependent manner. The highest concentrations were measured in vaginal fluid (10 to 10 ng/ml), followed by vaginal tissue (10 to 10 ng/ml). Both of these concentration ranges are several orders of magnitude above the reported half-maximal inhibitory concentrations. The lowest concentration was measured in serum (<10 ng/ml). The 5P12-RANTES pharmacokinetic data are similar to those reported previously for other candidate microbicides. These data, coupled with 5P12-RANTES's potency at picomolar concentrations, its strong barrier to resistance, and the full protection that it was observed to provide in a rhesus macaque vaginal challenge model, support the continued development of 5P12-RANTES as a microbicide.
5P12-RANTES 是一种趋化因子类似物，能够强有力地阻断 HIV CCR5 核心受体，目前正被开发为阴道和直肠用杀微生物剂，以预防 HIV 的性传播。在这里，我们报告了绵羊单次阴道凝胶给药后 5P12-RANTES 的首个药代动力学数据。通过流变学、可推注性和释放试验评估了含有低（1.24mg/ml）、中（6.18mg/ml）和高（32.0mg/ml；混悬型凝胶）浓度 5P12-RANTES 的水性凝胶制剂。在给绵羊阴道凝胶给药后，在 96 小时内测量了阴道液、阴道组织和血清中的 5P12-RANTES 浓度。所有凝胶均表现出非牛顿假塑性行为，高浓度凝胶的粘度和内聚结构大于中浓度和低浓度凝胶。在释放试验中，低浓度和中浓度凝胶在 72 小时后释放了超过 90%的 5P12-RANTES。对于高浓度凝胶，由于在冻干过程中蛋白质变性和/或随后在凝胶基质中蛋白质的溶剂化作用，检测到约 50%的 5P12-RANTES。在绵羊中，阴道液、阴道组织和血清中的 5P12-RANTES 浓度呈剂量依赖性增加。阴道液中的浓度最高（10 到 10ng/ml），其次是阴道组织（10 到 10ng/ml）。这些浓度范围均高于报道的半数最大抑制浓度好几个数量级。血清中的浓度最低（<10ng/ml）。5P12-RANTES 的药代动力学数据与其他候选杀微生物剂先前报道的数据相似。这些数据加上 5P12-RANTES 在皮摩尔浓度下的效力、其对耐药性的强大屏障以及在恒河猴阴道挑战模型中观察到的完全保护作用，支持继续开发 5P12-RANTES 作为杀微生物剂。
