Department of Internal Medicine, Nyon Hospital (GHOL), Nyon, Switzerland.
Antimicrobial Pharmacodynamics and Therapeutics Group, Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
Br J Clin Pharmacol. 2024 Sep;90(9):2079-2091. doi: 10.1111/bcp.16154. Epub 2024 Jun 25.
Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake 'traditional' pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co-medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolized by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co-medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co-medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk.
长效注射（LAI）卡替拉韦和利匹韦林用于 HIV 治疗，以及 LAI 卡替拉韦用于 HIV 暴露前预防，正在全球许多国家推出。由于暴露时间延长，进行“传统”药代动力学研究具有挑战性，目前的指南源自其口服等效物或基于生理学的药代动力学研究。本综述旨在考虑卡替拉韦和利匹韦林的药代动力学特征，并描述在非洲环境中与常见伴随药物预期发生的药物-药物相互作用（DDI）。相关伴随药物是从世界卫生组织 2021 年基本药物清单中确定的。在 PubMed 上以英文发表的所有关于 LAI 卡替拉韦和利匹韦林与 DDI 相关的原始人体和基于生理学的药代动力学研究，均进行了回顾。还审查了利物浦 HIV 相互作用数据库（https://www.hiv-druginteractions.org/checker）。LAI 卡替拉韦和利匹韦林的半衰期分别为 6-12 周和 13-28 周。卡替拉韦主要由 UDP-葡萄糖醛酸转移酶（UGT）-1A1 代谢，利匹韦林由细胞色素 P450（CYP）-3A4 代谢。LAI 卡替拉韦和利匹韦林本身发生相互作用的风险较低，因为它们不会诱导或抑制主要的药物代谢酶。然而，它们是由于伴随药物代谢酶诱导而发生的相互作用的受害者。值得注意的禁忌伴随药物包括利福平、卡马西平、苯妥英、氟氯西林和灰黄霉素，它们诱导 CYP3A4 和/或 UGT1A1，导致利匹韦林和/或卡替拉韦的临床显著浓度降低。除了病毒学失败外，DDI 导致的治疗浓度不足可导致出现耐药性。临床医生应意识到潜在的 DDI，并适当告知接受 LAI 卡替拉韦/利匹韦林治疗的患者，以最大限度降低风险。
