Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
J Control Release. 2019 Oct;311-312:201-211. doi: 10.1016/j.jconrel.2019.09.001. Epub 2019 Sep 3.
Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25 weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug half-life and improve tissue biodistribution. These results warrant further development for human use.
抗逆转录病毒疗法需要终身每日剂量，以达到病毒抑制、恢复免疫功能和提高生活质量的目的。作为一种治疗选择，长效（LA）抗逆转录病毒可以在血液中维持较长时间的治疗药物浓度。最近 LA 注射用卡替拉韦和利匹韦林的临床试验的成功突出了这些新治疗选择的出现。进一步优化可以提高给药频率、降低注射体积，并促进药物组织分布。为此，我们报告了一组旨在维持药物血浆浓度和改善组织生物分布的 RPV 前药的合成。先导前药 M3RPV 被纳米化为稳定的 LA 可注射 NM3RPV。NM3RPV 治疗在 BALB/cJ 小鼠单次肌肉注射后，可使 RPV 血浆浓度在 25 周内保持在蛋白校正的 90%抑制浓度以上，并在组织中有大量蓄积。与天然药物制剂相比，NM3RPV 使 RPV 的表观半衰期和平均停留时间分别延长了 13 倍和 26 倍。综上所述，提供了证明纳米化 RPV 前药可以延长药物的表观半衰期并改善组织生物分布的概念验证。这些结果值得进一步开发用于人类使用。
