De Nicolò Amedeo, Palermiti Alice, Mugerwa Henry, Nakabuye Shamim, Namusanje Josephine, Kobusingye Josephine, Odoch Denis, Lamorde Mohammed, Kengo Allan, Denti Paolo, Gausi Kamunkhwala, Maartens Gary, McIlleron Helen, Wiesner Lubbe, Khoo Saye, Waitt Catriona, D'Avolio Antonio
Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, Italy.
Joint Clinical Research Centre, Kampala, Uganda.
Clin Pharmacol Ther. 2025 May;117(5):1393-1402. doi: 10.1002/cpt.3572. Epub 2025 Jan 31.
Ritonavir-boosted atazanavir is a victim of drug-drug interaction with rifampicin, a key component of antitubercular treatment. In a recent dose escalation clinical trial, we showed that increasing atazanavir/ritonavir to 300/100 mg b.i.d. compensates for reduced drug exposure in plasma due to rifampicin, but the intracellular effects remained unexplored. This sub-study investigated the intracellular penetration of atazanavir/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMC). Twenty-six healthy volunteers living with HIV, virologically suppressed, and taking atazanavir/ritonavir containing regimens were enrolled. The trial consisted of four sequential periods: PK1, participants were on atazanavir/ritonavir 300/100 mg q.d.; at PK2, rifampicin 600 mg q.d. and dolutegravir 50 mg b.i.d. were added (2 weeks); at PK3, atazanavir/ritonavir dose was increased to 300/100 mg b.i.d. (1 week); at PK4, rifampicin dose was doubled (1 week). Atazanavir, ritonavir, and dolutegravir were quantified in plasma and PBMC using LC-MS/MS methods to evaluate steady-state concentrations at the end of each period. Atazanavir/ritonavir dose escalation successfully restored intracellular concentrations comparable to those observed without rifampicin, with a geometric mean ratio of 0.99 (CI 0.72-1.41) for atazanavir at PK3 compared with PK1. The intracellular concentration of dolutegravir increased significantly with atazanavir/ritonavir dose escalation, similar to plasma. Finally, further, increasing the rifampicin dose did not show an additional impact on atazanavir/ritonavir concentrations in PBMC. The study confirms that increasing the ATV/r dose can be an effective strategy for compensating rifampicin effects even at the intracellular level, supporting its use in clinical settings.
利托那韦增强的阿扎那韦是抗结核治疗的关键成分利福平所致药物相互作用的受害者。在最近一项剂量递增临床试验中，我们发现将阿扎那韦/利托那韦剂量增至300/100mg每日两次，可弥补利福平导致的血浆药物暴露减少，但细胞内效应仍未得到探索。这项子研究调查了阿扎那韦/利托那韦和多替拉韦进入外周血单核细胞（PBMC）的细胞内渗透情况。招募了26名病毒学抑制且正在服用含阿扎那韦/利托那韦方案的HIV感染者。试验包括四个连续阶段：PK1阶段，参与者服用阿扎那韦/利托那韦300/100mg每日一次；PK2阶段，添加利福平600mg每日一次和多替拉韦50mg每日两次（持续2周）；PK3阶段，将阿扎那韦/利托那韦剂量增至300/100mg每日两次（持续1周）；PK4阶段，将利福平剂量加倍（持续1周）。采用液相色谱-串联质谱法（LC-MS/MS）对血浆和PBMC中的阿扎那韦、利托那韦以及多替拉韦进行定量，以评估各阶段结束时的稳态浓度。阿扎那韦/利托那韦剂量递增成功恢复了细胞内浓度，与未使用利福平的情况相当，PK3阶段阿扎那韦的几何平均比值为0.99（95%置信区间0.72 - 1.41），与PK1阶段相比。随着阿扎那韦/利托那韦剂量递增，多替拉韦的细胞内浓度显著增加，与血浆情况类似。最后，进一步增加利福平剂量对PBMC中阿扎那韦/利托那韦浓度未显示出额外影响。该研究证实，增加阿扎那韦/利托那韦剂量即使在细胞内水平也是补偿利福平效应的有效策略，支持其在临床环境中的应用。
