Thoueille Paul, Saldanha Susana Alves, Schaller Fabian, Choong Eva, Veuve François, Munting Aline, Cavassini Matthias, Braun Dominique, Günthard Huldrych F, Duran Ramirez Jessy J, Surial Bernard, Furrer Hansjakob, Rauch Andri, Ustero Pilar, Calmy Alexandra, Stöckle Marcel, Di Benedetto Caroline, Bernasconi Enos, Schmid Patrick, Marzolini Catia, Girardin François R, Buclin Thierry, Decosterd Laurent A, Guidi Monia
Service of Clinical Pharmacology, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Front Pharmacol. 2024 Nov 15;15:1437400. doi: 10.3389/fphar.2024.1437400. eCollection 2024.
The pharmacokinetics of long-acting rilpivirine has mostly been studied in clinical trials, which do not fully address the uncertainties that arise in routine clinical situations.
Our population analysis aims to establish percentile curves for rilpivirine concentrations in people with HIV (PWH) followed-up in a routine clinical setting, while identifying patient-related factors that may influence rilpivirine exposure. A total of 238 PWH enrolled in our nationwide multicenter observational study contributed to 1038 concentrations (186 and 852 concentrations after oral and intramuscular injection, respectively).
Rilpivirine pharmacokinetics were best described by a two-compartment model with an oral to intramuscular relative bioavailability factor. A simple zero-order absorption process was retained for oral administration while a parallel first-order absorption was used for intramuscular administration, with 27.6% of the dose released via a fast absorption pathway and the remaining fraction via a slow absorption pathway. Our model estimated that long-acting rilpivirine reaches steady-state after 2.5 years and has an elimination half-life of 18 weeks, consistent with published estimates. In females, a 45.6% reduction in the proportion of the dose absorbed via the rapid absorption pathway was observed. However, this resulted in no more than 15% difference in trough concentrations (C) compared to males, which was not considered to be clinically relevant.
Overall, our model-based simulations showed that only approximately 50% of long-acting rilpivirine C would be above the 50 ng/mL threshold associated with optimal therapeutic response, while approximately 85% of C would be above the first quartile of concentrations observed in Phase III trials (32 ng/mL).
长效利匹韦林的药代动力学大多在临床试验中进行了研究，但这些试验并未充分解决常规临床情况下出现的不确定性。
我们的群体分析旨在为在常规临床环境中接受随访的艾滋病毒感染者（PWH）建立利匹韦林浓度的百分位数曲线，同时确定可能影响利匹韦林暴露的患者相关因素。我们在全国范围内的多中心观察性研究中招募的238名PWH贡献了1038个浓度数据（口服和肌肉注射后分别为186个和852个浓度数据）。
利匹韦林的药代动力学最好用具有口服至肌肉注射相对生物利用度因子的二室模型来描述。口服给药采用简单的零级吸收过程，而肌肉注射采用平行一级吸收，27.6%的剂量通过快速吸收途径释放，其余部分通过缓慢吸收途径释放。我们的模型估计，长效利匹韦林在2.5年后达到稳态，消除半衰期为18周，与已发表的估计值一致。在女性中，观察到通过快速吸收途径吸收的剂量比例降低了45.6%。然而，与男性相比，这导致谷浓度（C）的差异不超过15%，这不被认为具有临床相关性。
总体而言，我们基于模型的模拟表明，只有约50%的长效利匹韦林C会高于与最佳治疗反应相关的50 ng/mL阈值，而约85%的C会高于III期试验中观察到的浓度的第一四分位数（32 ng/mL）。
