Pfister Marc, Labbé Line, Hammer Scott M, Mellors John, Bennett Kara K, Rosenkranz Susan, Sheiner Lewis B
Department of Laboratory Medicine and Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, California 94143, USA.
Antimicrob Agents Chemother. 2003 Jan;47(1):130-7. doi: 10.1128/AAC.47.1.130-137.2003.
The present population pharmacokinetic (PK) and pharmacodynamic (PD) study modeled the effects of covariates including drug adherence and the coadministration of protease inhibitors (PIs) on the pharmacokinetics of efavirenz (EFV) and the relationship between EFV exposure and virological failure in patients who failed initial PI treatment in Adult AIDS Clinical Trial Group (AACTG) study 398. We also report on the population PKs of the PIs nelfinavir (NFV) and indinavir (IDV). AACTG study 398 patients received EFV, amprenavir, adefovir dipivoxil, and abacavir and were randomized to take, in addition, one of the following: NFV, IDV, saquinavir (SQV), or placebo. The PK databases consisted of 531 EFV concentrations (139 patients), 219 NFV concentrations (75 patients), and 66 IDV concentrations (11 patients). Time to virological failure was ascertained for all patients in the PK databases. PK data were fit with a population PK model that assumed exclusive hepatic elimination (the well-stirred model). Notable findings with respect to EFV PK and PD are as follows. (i) The hepatic clearance of EFV is unaltered by NFV, IDV, or SQV coadministration. (ii) The hepatic clearance of EFV appears to be 28% higher in white non-Hispanics than in African Americans and Hispanics (P = 0.03). (iii) Higher adherence scores (as measured with the Medication Event Monitoring System) are associated with marginally increased levels of exposure to EFV. (iv) In patients with no prior experience with nonnucleoside reverse transcriptase inhibitors (NNRTIs), a given percent increase in the oral clearance (CL/F) of EFV is associated with a greater percent increase in the hazard of virological failure (P < 0.0003). Among NNRTI-experienced patients, however, hazard is relatively uncorrelated with EFV CL/F.
本群体药代动力学（PK）和药效学（PD）研究建立了协变量效应模型，这些协变量包括药物依从性以及蛋白酶抑制剂（PI）的联合使用，以研究其对依非韦伦（EFV）药代动力学的影响，以及在成人艾滋病临床试验组（AACTG）398研究中初始PI治疗失败的患者中EFV暴露量与病毒学失败之间的关系。我们还报告了PI奈非那韦（NFV）和茚地那韦（IDV）的群体PK情况。AACTG 398研究中的患者接受了EFV、安普那韦、阿德福韦酯和阿巴卡韦治疗，并被随机分配额外服用以下药物之一：NFV、IDV、沙奎那韦（SQV）或安慰剂。PK数据库包含531个EFV浓度数据（139名患者）、219个NFV浓度数据（75名患者）和66个IDV浓度数据（11名患者）。确定了PK数据库中所有患者的病毒学失败时间。PK数据采用假设肝脏为唯一消除途径的群体PK模型（充分搅拌模型）进行拟合。关于EFV PK和PD的显著发现如下：（i）联合使用NFV、IDV或SQV不会改变EFV的肝脏清除率。（ii）非西班牙裔白人中EFV的肝脏清除率似乎比非裔美国人和西班牙裔高28%（P = 0.03）。（iii）较高的依从性评分（通过用药事件监测系统测量）与EFV暴露水平的小幅升高相关。（iv）在没有非核苷类逆转录酶抑制剂（NNRTI）使用经验的患者中，EFV口服清除率（CL/F）给定百分比的增加与病毒学失败风险的更大百分比增加相关（P < 0.0003）。然而，在有NNRTI使用经验的患者中，风险与EFV CL/F相对不相关。
