Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients
Influence of the Cytochrome P450 2B6 Genotype on Population Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus Patients
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DOI：
10.1128/aac.01537-08
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发表时间：
2009-07-01
影响因子：
4.9
通讯作者：
Garcia, Maria J.
中科院分区：
文献类型：
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作者：
Cabrera, Salvador E.;Santos, Dolores;Garcia, Maria J.
根据人类免疫缺陷病毒（HIV）阳性患者的治疗药物监测数据，采用非线性混合效应模型建立了依法韦仑的群体药代动力学模型。采用高效液相色谱法和紫外检测器分析了131例患者（n = 375）的依法韦仑血药浓度。根据一室模型估计药代动力学参数。分析了性别、年龄、总体重、身高、体重指数和HIV治疗的影响。在一个亚组的32例患者中，细胞色素P450 2B 6基因（CYP 2B 6），CYP 3A 4和MDR 1的遗传多态性也进行了研究。依法韦仑口服清除率和表观分布容积分别为9.50升/小时和311升。该模型仅包括CYP 2B 6多态性对依法韦仑清除率的影响;该协变量使清除率的受试者间变异性降低约27%。表现出G/T和T/T CYP 2B 6多态性的患者显示出依法韦仑清除率比在没有这些多态性（G/G）的患者中观察到的低约50%和75%。因此，为了获得治疗范围内的EFV稳态浓度（1至4 mg/L），建议分别对中间代谢型或弱代谢型患者实施剂量逐渐减少至400或200 mg/天。然而，在该模型的药代动力学参数中观察到的剩余个体间变异性强调了剂量个体化的必要性，以避免依法韦仑暴露不足，并建议谨慎使用这些推荐剂量，并通过治疗药物监测和临床疗效进行确认。群体模型可以在药代动力学临床软件中实现，用于通过使用贝叶斯方法进行剂量优化。
A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n = 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6), CYP3A4, and MDR1 were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect of CYP2B6 polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/T CYP2B6 polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.