Merck & Co., Inc, Kenilworth, NJ, USA.
J Clin Pharm Ther. 2020 Oct;45(5):1098-1105. doi: 10.1111/jcpt.13182. Epub 2020 Jun 5.
Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection.
After confirmation of tolerability and safety of oral doravirine, 36 participants were randomized 1:1:1 to receive IM doravirine 200 mg as Treatment A (1 × 1 mL, 20% [200 mg/mL] suspension), B (1 × 0.66 mL, 30% [300 mg/mL] suspension) or C (2 × 0.5 mL, 20% suspension). Blood samples were taken as venous plasma, venous dried blood spots (DBS) and fingerstick DBS.
Plasma concentration-time profiles following IM treatments demonstrated rapid initial doravirine release, with initial peak 4 days post-injection, followed by decline over the next ~6 days; a second peak was reached at ~24-36 days, corresponding to prolonged and sustained release, with measurable concentrations up to Day 183. Treatment C was associated with highest peak concentrations and shortest time to maximum concentration. Elimination half-lives for all IM formulations were prolonged versus oral administration (46-58 days vs ~11-15 hours). Oral doravirine and IM doravirine were generally well tolerated; injection-site pain was the most common adverse event for IM doravirine. Doravirine concentrations from DBS samples showed strong correlations to venous plasma concentrations.
Novel doravirine LAP IM injection formulations investigated in this study demonstrated sustained plasma doravirine concentrations over a course of >20 weeks.
多伟拉韦是一种非核苷类逆转录酶抑制剂，用于治疗人类免疫缺陷病毒（HIV-1）感染。这项在健康成年人中进行的 1 期研究调查了多伟拉韦长效肌内（IM）注射制剂的药代动力学、安全性和耐受性。
在口服多伟拉韦耐受和安全性得到确认后，36 名参与者按 1:1:1 的比例随机分为三组，分别接受 IM 多伟拉韦 200mg：A 组（1×1mL，20%[200mg/mL]混悬剂）、B 组（1×0.66mL，30%[300mg/mL]混悬剂）或 C 组（2×0.5mL，20%混悬剂）。采集静脉血浆、静脉干血斑（DBS）和指尖 DBS 作为血样。
IM 治疗后的血浆浓度-时间曲线显示，多伟拉韦迅速释放初始剂量，初始峰值在注射后约 4 天，随后在接下来的约 6 天内下降；在约 24-36 天达到第二个峰值，这与延长和持续释放相对应，可在第 183 天检测到药物浓度。C 组的峰浓度最高，达到最大浓度的时间最短。所有 IM 制剂的消除半衰期均长于口服给药（46-58 天 vs11-15 小时）。口服和 IM 多伟拉韦通常具有良好的耐受性；注射部位疼痛是 IM 多伟拉韦最常见的不良反应。DBS 样本中的多伟拉韦浓度与静脉血浆浓度有很强的相关性。
本研究中研究的新型多伟拉韦长效肌内注射制剂在 20 多周的疗程中显示出持续的血浆多伟拉韦浓度。
