Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
Quantitative Solutions, Menlo Park, CA, USA.
Clin Pharmacokinet. 2017 Oct;56(10):1173-1183. doi: 10.1007/s40262-016-0504-2.
Daclatasvir is a potent, pangenotypic once-daily hepatitis C virus (HCV) NS5A inhibitor that is approved for the treatment of chronic HCV infection. The objective of this analysis was to characterize the pharmacokinetics of daclatasvir in subjects with chronic HCV infection.
A population pharmacokinetic (PPK) model was developed to evaluate effects of covariates on daclatasvir pharmacokinetics in subjects with chronic HCV infection (n = 2149 from 11 studies). All significant demographic, laboratory, prognostic and treatment covariates (p < 0.05) from univariate screening were included in the full model. The final model was reached by backward elimination (p < 0.001) and simulations were performed to further evaluate the effects of covariates on daclatasvir exposures. The plasma pharmacokinetics of daclatasvir was described by a two-compartment model with linear elimination. Absorption was modeled as a zero-order release followed by a first-order absorption into the central compartment.
The typical value of apparent clearance (CL/F) was 5.7 L/h (1.58% relative standard error [RSE]) and of apparent volume of the central compartment (V /F) was 58.6 L (2.00% RSE). Modest inter-individual variability was estimated for CL/F (35.1%) and V /F (29.5%). Statistically significant covariates in the final model were sex, race, virus genotype, baseline creatinine clearance, and alanine aminotransferase (ALT) on CL/F and sex, race, and body weight on V /F. Covariate effects demonstrated a 30% higher area under the plasma concentration-time curve at steady state (AUC) in female subjects; effects of all other covariates were <16%.
The model adequately described the daclatasvir pharmacokinetics and estimated relatively small covariate effects. Considering the exposure range for the therapeutic dose of daclatasvir 60 mg once daily and the favorable safety profile, the small difference in exposures due to these covariates is not considered clinically relevant.
达卡他韦是一种强效、泛基因型的每日一次丙型肝炎病毒（HCV）NS5A 抑制剂，已被批准用于治疗慢性 HCV 感染。本分析的目的是描述慢性 HCV 感染患者中达卡他韦的药代动力学特征。
建立了一个群体药代动力学（PPK）模型，以评估对慢性 HCV 感染患者达卡他韦药代动力学的影响（来自 11 项研究的 2149 例患者）。所有有统计学意义的人口统计学、实验室、预后和治疗相关的协变量（单侧筛选 p<0.05）均被纳入全模型。采用后向消除法（p<0.001）得出最终模型，并进行模拟以进一步评估协变量对达卡他韦暴露的影响。达卡他韦的血浆药代动力学采用线性消除的两室模型进行描述。吸收采用零级释放，随后以一级吸收进入中央室。
典型的表观清除率（CL/F）值为 5.7 L/h（相对标准误差[RSE]为 1.58%），中央室表观容积（V/F）值为 58.6 L（RSE 为 2.00%）。CL/F 和 V/F 的个体间差异估计分别为 35.1%和 29.5%。最终模型中的统计学显著协变量为性别、种族、病毒基因型、基线肌酐清除率和丙氨酸氨基转移酶（ALT）对 CL/F 的影响，以及性别、种族和体重对 V/F 的影响。协变量效应表明，女性患者的稳态时血浆浓度-时间曲线下面积（AUC）增加了 30%；其他所有协变量的影响均<16%。
该模型充分描述了达卡他韦的药代动力学特征，且估计了相对较小的协变量效应。考虑到达卡他韦 60 mg 每日一次的治疗剂量的暴露范围和良好的安全性特征，这些协变量导致的暴露差异无临床意义。
