多替拉韦的群体药代动力学：真实环境下药物相互作用的影响。
Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.
机构信息
Service of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Bugnon 17, Lausanne, Switzerland.
Service of Clinical Chemistry, University Hospital Centre and University of Lausanne, Bugnon 46, Lausanne, Switzerland.
出版信息
J Antimicrob Chemother. 2019 Sep 1;74(9):2690-2697. doi: 10.1093/jac/dkz217.
OBJECTIVES
Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition.
METHODS
A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions.
RESULTS
A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively.
CONCLUSIONS
Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.
目的
由于具有强大的抗病毒活性、较高的遗传屏障和良好的耐受性，多拉韦林得到了广泛应用。本研究旨在描述真实环境中多拉韦林的药代动力学特征和变异性，并确定影响多拉韦林处置的个体因素和合并用药。
方法
使用 NONMEM® 建立群体药代动力学模型。测试了相关的人口统计学因素、临床因素和合并用药，以确定它们是否为潜在的协变量。基于最终模型进行模拟，以比较在存在药物相互作用的情况下，标准和替代剂量方案下预期的多拉韦林浓度。
结果
从 521 名处于稳态条件下的 HIV 感染个体中收集了总共 620 个多拉韦林血药浓度。多拉韦林药代动力学最好用单室模型加一级吸收和消除来描述。典型的多拉韦林表观清除率（CL/F）为 0.93 L/h，个体间差异为 32%，表观分布容积为 20.2 L，吸收速率常数固定为 2.24 h-1。年龄较大、体重较高和当前吸烟与更高的 CL/F 相关。阿扎那韦合用使多拉韦林 CL/F 降低了 38%，而达芦那韦则使 CL/F 适度增加了 14%。利福平合用的影响最大。模拟表明，与无利福平的标准剂量 50 mg/24 h 相比，利福平合用 50 mg/12 h 时多拉韦林的平均谷浓度低 63%。利福平合用 100 mg/24 h 和 100 mg/12 h 时的平均谷浓度分别比无利福平的标准剂量低 92%和 25%。
结论
多拉韦林与利福平联合治疗的患者可能受益于治疗药物监测和个体化剂量增加，在某些情况下可达 100 mg/12 h。
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