Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
Clin Pharmacokinet. 2011 Aug;50(8):531-40. doi: 10.2165/11592660-000000000-00000.
Pharmacokinetic studies of antiretroviral drugs are often conducted in adult healthy subjects, and the results are extrapolated to HIV/AIDS patients. HIV/AIDS, however, is known to cause morphological and physiological changes that may alter the pharmacokinetics of antiretroviral drugs. We examined the effect of HIV/AIDS on the pharmacokinetics of efavirenz in Ugandans.
After a first oral dose of efavirenz 600 mg in treatment-naïve HIV-infected patients, blood samples were collected at nine time points up to 24 hours. The plasma-concentration time data from these patients were merged with previously reported data from adult healthy subjects. Population pharmacokinetic models were fitted to the data, using NONMEM VI software. Covariate analyses were performed to estimate the effects of HIV/AIDS disease, demographic characteristics (sex, bodyweight, age), biochemical variables (serum creatinine, urea, alanine aminotransferase) and pharmacogenetic variation in cytochrome P450 (CYP) 2B6, CYP3A5 and adenosine triphosphate-binding cassette, sub-family B, member 1 (ABCB1) on the population pharmacokinetic parameters.
Efavirenz plasma concentration-time data obtained from 29 HIV-1-infected, treatment-naïve patients were merged with previously reported data from 32 adult healthy subjects. The model identified sex and HIV/AIDS disease as statistically significant categorical predictors of efavirenz pharmacokinetics. Females were predicted to have a 2-fold higher volume of distribution of the peripheral compartment after oral administration (V(2)/F) than males (95% CI 1.53, 2.63), while HIV/AIDS patients were found to have 30% lower relative bioavailability (95% CI 18.7, 40.7) than healthy subjects. The increased V(2)/F in females resulted in a 2-fold longer elimination half-life than in males.
On the basis of the findings of this analysis, we conclude that, apart from bodyweight-based differences, both HIV/AIDS disease and sex affect efavirenz pharmacokinetics in Ugandans. HIV/AIDS disease is associated with reduced relative bioavailability of efavirenz. We recommend that findings from healthy subject studies be confirmed in HIV/AIDS patients and that caution be applied in direct extrapolation of exposure data to the target patient population.
抗逆转录病毒药物的药代动力学研究通常在成年健康受试者中进行，研究结果被推断用于艾滋病毒/艾滋病患者。然而，艾滋病毒/艾滋病已知会引起形态和生理变化，从而可能改变抗逆转录病毒药物的药代动力学。我们研究了艾滋病毒/艾滋病对乌干达人体内依非韦伦药代动力学的影响。
在未经治疗的 HIV 感染患者中首次口服依非韦伦 600mg 后，在 24 小时内采集 9 个时间点的血样。将这些患者的血浆浓度-时间数据与以前报告的成年健康受试者的数据合并。使用 NONMEM VI 软件对数据进行群体药代动力学模型拟合。进行协变量分析，以评估艾滋病毒/艾滋病疾病、人口统计学特征（性别、体重、年龄）、生化变量（血清肌酐、尿素、丙氨酸氨基转移酶）和细胞色素 P450（CYP）2B6、CYP3A5 和三磷酸腺苷结合盒，亚家族 B，成员 1（ABCB1）的遗传变异对群体药代动力学参数的影响。
将 29 名未经治疗的 HIV-1 感染的患者的依非韦伦血浆浓度-时间数据与以前报告的 32 名成年健康受试者的数据合并。该模型确定了性别和艾滋病毒/艾滋病疾病是依非韦伦药代动力学的统计学上显著的分类预测因子。与男性相比，女性口服后外周室分布体积（V2/F）高 2 倍（95%CI 1.53，2.63），而艾滋病毒/艾滋病患者的相对生物利用度低 30%（95%CI 18.7，40.7）比健康受试者。女性的 V2/F 增加导致消除半衰期延长 2 倍。
基于本分析的结果，我们得出结论，除了基于体重的差异外，艾滋病毒/艾滋病疾病和性别都会影响乌干达人体内依非韦伦的药代动力学。艾滋病毒/艾滋病与依非韦伦的相对生物利用度降低有关。我们建议在艾滋病毒/艾滋病患者中确认健康受试者研究的结果，并在将暴露数据直接外推至目标患者人群时谨慎使用。
