Hospices Civils de Lyon, GHS-Centre de Biologie Sud, Pierre Bénite.
Hospices Civils de Lyon, Maladies Infectieuses et Tropicales, Hôpital Croix-Rousse.
Ther Drug Monit. 2019 Aug;41(4):444-451. doi: 10.1097/FTD.0000000000000618.
There are growing concerns about dolutegravir (DTG)-related neuropsychiatric adverse events and about differences in the characteristics of people living with HIV infection (PLWH) potentially associated with higher risks of said side effects. Several studies have shown that DTG was stopped more frequently among women, older PLWH, and PLWH who initiated abacavir (ABC) at the same time. This study aimed to clarify the factors affecting the pharmacokinetics (PKs) of DTG in a real-life cohort of PLWH using a population PK approach.
The model-building strategy was based on a previously published model developed from premarketing trials (1-compartment model with first-order absorption and a lag time). Sparse therapeutic drug monitoring data were obtained from a real-life cohort of 279 PLWH, and population PK analysis was performed using Monolix software. A stepwise covariate model-building strategy was used to evaluate any relevant effects of age, body weight, gender, total bilirubin, smoking status, formulations of DTG, morning versus evening dosing, backbone therapy, and other comedications including CYP/UGT inducers/inhibitors.
For a typical 70-kg PLWH, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.748 L/h and 14.6 L, respectively. Of the demographic factors evaluated, body weight was a significant covariate for CL/F and for V/F. Smokers had a 17% higher CL/F relative to nonsmokers. Both strong enzyme inhibitors (eg, atazanavir) and inducers (eg, rifampicin) had marked effects on DTG exposure, with potential clinical implications. Ritonavir-boosted darunavir was found to moderately increase clearance of DTG by 23%. No significant effect of ABC-based backbone therapy was observed on the PK parameters of DTG.
Our results did not support the hypothesis that ABC, by competing with the DTG metabolic pathway, may significantly increase DTG exposure leading to potential drug toxicity.
人们越来越关注多替拉韦（DTG）相关的神经精神不良事件，以及与更高副作用风险相关的艾滋病毒感染者（PLWH）特征的差异。一些研究表明，在女性、年龄较大的 PLWH 和同时开始使用阿巴卡韦（ABC）的 PLWH 中，DTG 更频繁地被停用。本研究旨在使用群体药代动力学方法，在真实的 PLWH 队列中阐明影响 DTG 药代动力学（PKs）的因素。
模型构建策略基于来自上市前试验的先前发表的模型（具有一级吸收和滞后时间的 1 室模型）。从真实的 PLWH 队列中获得了稀疏的治疗药物监测数据，并使用 Monolix 软件进行了群体 PK 分析。使用逐步协变量模型构建策略评估年龄、体重、性别、总胆红素、吸烟状况、DTG 制剂、早晚剂量、骨干治疗以及包括 CYP/UGT 诱导剂/抑制剂在内的其他合并用药对任何相关影响。
对于典型的 70 公斤 PLWH，表观清除率（CL/F）和表观分布容积（V/F）分别为 0.748 L/h 和 14.6 L。在评估的人口统计学因素中，体重是 CL/F 和 V/F 的重要协变量。与不吸烟者相比，吸烟者的 CL/F 高 17%。强酶抑制剂（如阿扎那韦）和诱导剂（如利福平）对 DTG 暴露均有显著影响，具有潜在的临床意义。发现利托那韦增强的达芦那韦适度增加了 DTG 清除率 23%。基于 ABC 的骨干治疗对 DTG 的 PK 参数没有显著影响。
我们的结果不支持 ABC 通过与 DTG 代谢途径竞争而显著增加 DTG 暴露导致潜在药物毒性的假设。
