Zhang Jianping, Hayes Siobhán, Sadler Brian M, Minto Ilisse, Brandt Julie, Piscitelli Steve, Min Sherene, Song Ivy H
Clinical Pharmacology, GlaxoSmithKline, Research Triangle Park, NC, USA.
ICON, Marlow, UK.
Br J Clin Pharmacol. 2015 Sep;80(3):502-14. doi: 10.1111/bcp.12639. Epub 2015 Jul 14.
Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates.
A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10-50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine.
The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h(-1) , 17.4 l, 2.24 h(-1) , and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co-infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis.
A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients.
多替拉韦是最新获批用于治疗HIV的整合酶抑制剂，在具有广泛治疗经验的患者群体中已显示出强大的抗病毒活性。本分析旨在描述初治患者中多替拉韦的群体药代动力学特征，并评估患者协变量的影响。
采用非线性混合效应建模方法，基于来自三项2/3期试验的563例HIV感染的初治成年患者的数据，建立群体药代动力学模型。这些患者单独接受多替拉韦（每日一次，剂量为10 - 50mg）或与阿巴卡韦/拉米夫定或替诺福韦/恩曲他滨联合使用。
多替拉韦的药代动力学可用具有一级吸收、吸收延迟时间和一级消除的线性单室模型充分描述。表观清除率、表观分布容积、吸收速率常数和吸收延迟时间的群体估计值分别为0.901 l h(-1)、17.4 l、2.24 h(-1)和0.263 h。体重、吸烟状况、年龄和总胆红素是清除率的预测因子，体重是分布容积的预测因子，性别是生物利用度的预测因子。然而，这些协变量对多替拉韦稳态血浆暴露的影响程度相对较小（<32%），且不被认为具有临床意义。在本分析中，种族/民族、HBV/HCV合并感染、CDC分类、白蛋白、肌酐清除率、丙氨酸转氨酶或天冬氨酸转氨酶均未影响多替拉韦的药代动力学。
已建立了一个能充分描述多替拉韦药代动力学特征的群体模型。在HIV感染的初治患者中，无需根据患者协变量调整多替拉韦剂量。
