Long-acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real-world reference percentile curves of cabotegravir concentrations, accounting for patient-related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one-compartment model with distinct first order-absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady-state of 8 months and an elimination half-life of 4.6 weeks for long-acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model-based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4-fold protein-adjusted 90% inhibitory target concentration.

中文翻译：

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真实世界艾滋病毒感染者口服和长效肌肉注射后卡博特韦的群体药代动力学

长效卡博特韦主要在严格的临床试验框架下进行研究，这并不一定反映常规临床环境中艾滋病毒感染者（PWH）的情况。目前的群体药代动力学分析旨在建立卡博特韦浓度的真实世界参考百分位曲线，考虑可能影响卡博特韦暴露的患者相关因素。第二个目标是模拟是否可以在特定亚群中考虑调整卡博特韦的给药间隔。总体而言，238 名 PWH 贡献了 1,038 个卡博特韦水平（初始口服给药阶段为 186 个，肌肉注射后为 852 个）。使用单室模型最好地描述了卡博特韦的药代动力学，该模型具有独特的口服和肌肉注射一级吸收以及相同的体积和清除率。我们的模型显示，与之前报道的相比，吸收速度快了近 40%，清除速度高了 30%，长效卡博特韦达到稳态的时间为 8 个月，消除半衰期为 4.6 周。性别和体重指数显着影响吸收，体重影响清除。基于模型的模拟显示，肌肉注射负荷剂量后 4 周，女性中 cabotegravir 的谷浓度降低了 25%，但在维持后期则升高了 42%。最后，模拟表明，在女性中，尽管卡博特韦浓度明显较高，但较长的注射间隔可能无法始终确保水平高于 4 倍蛋白质调整的 90% 抑制目标浓度。