Objectives To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration. Methods Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software. Results A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics. Conclusions The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.

中文翻译：

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利匹韦林长效制剂在健康受试者和 HIV 感染者肌肉内给药后的群体药代动力学

目的 表征肌内给药后利匹韦林长效 (LA) 制剂的群体药代动力学。方法从七项临床研究中获得丰富和稀疏的利匹韦林血浆浓度数据。总共从 986 名受试者（来自 I 期研究的 131 名健康受试者和来自 IIb/III 期研究的 855 名 HIV 感染者）收集了 18261 份利匹韦林样本。剂量范围为 300 至 1200 mg，作为单剂量或多剂量方案（每 4 或 8 周一次）。在 III 期研究中，开始注射 900 mg，然后每 4 周继续注射 600 mg。使用 NONMEM® 软件进行非线性混合效应建模。结果 具有线性消除和两条平行吸收途径（快速和慢速）的单室模型具有连续的零一级过程，充分捕获了 LA 制剂肌肉内给药后的 rilpivirine 触发器药代动力学。利匹韦林 LA 的估计表观消除半衰期为 200 天。评估的协变量（年龄、体重、BMI、性别、种族、健康状况和针头长度）均未对利匹韦林药代动力学产生临床相关影响。结论 群体药代动力学模型恰当地描述了利匹韦林 LA 肌内给药后利匹韦林血浆浓度的时间过程和相关变异性。每月方案包括一个口服导入期（rilpivirine 25 mg 片剂，每天一次，持续 4 周），然后开始注射 900 mg rilpivirine LA，然后每月继续注射 600 mg rilpivirine LA。协变量对 rilpivirine 药代动力学没有临床相关影响，这表明没有必要对特定亚组进行 rilpivirine LA 剂量调整。