Cammett Anna Maria, MacGregor Thomas R, Wruck Jan M, Felizarta Franco, Miailhes Patrick, Mallolas Josep, Piliero Peter J
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.
Antimicrob Agents Chemother. 2009 Oct;53(10):4147-52. doi: 10.1128/AAC.00460-09. Epub 2009 Jul 20.
Nevirapine is a nonnucleoside reverse transcriptase inhibitor used as part of combination therapy for human immunodeficiency virus (HIV) infection. Nevirapine may be prescribed for patients with hepatic fibrosis and cirrhosis. Significant autoinduction of cytochrome P450 3A4 and 2B6 following multiple dosing prompted an assessment of the metabolic profiles in patients with liver disease receiving chronic nevirapine therapy. HIV-infected patients with hepatic fibrosis who were receiving a stable antiretroviral regimen containing nevirapine for > or = 6 weeks had liver biopsy specimens assessed by Ishak histologic scoring and were grouped by severity (group 1, Ishak scores of 1 and 2; group 2, Ishak scores of 3 and 4; group 3, Ishak scores of 5 and 6). Steady-state trough nevirapine levels were determined for all patients, and additional measurements were obtained at 1, 2, and 4 h following nevirapine dosing for a subset of patients. The pharmacokinetics of nevirapine and its five metabolites were characterized, and a comparison of the results for the different Ishak groups was performed. Among 51 patients with hepatic fibrosis, the majority of whom were coinfected with hepatitis C virus or hepatitis B virus, differences between the maximum and the minimum observed plasma concentrations demonstrated a statistically significant flattening of the systemic exposure curves with progression from Ishak group 1 to Ishak group 2 or 3, suggesting a decrease in systemic clearance with the progression of liver disease. However, there were no significant differences in the trough and the maximum nevirapine concentrations between the Ishak groups. The metabolite profiles were also comparable across the Ishak groups. In HIV-infected patients who were chronically treated with nevirapine and who had various degrees of hepatic fibrosis, including cirrhosis, trough plasma nevirapine concentrations were not significantly increased, and thus, no dose adjustment is warranted.
奈韦拉平是一种非核苷类逆转录酶抑制剂，用于人类免疫缺陷病毒（HIV）感染的联合治疗。奈韦拉平可用于肝纤维化和肝硬化患者。多次给药后细胞色素P450 3A4和2B6的显著自身诱导促使对接受慢性奈韦拉平治疗的肝病患者的代谢谱进行评估。接受含奈韦拉平的稳定抗逆转录病毒方案≥6周的HIV感染肝纤维化患者，其肝活检标本采用Ishak组织学评分进行评估，并按严重程度分组（第1组，Ishak评分为1和2；第2组，Ishak评分为3和4；第3组，Ishak评分为5和6）。测定所有患者的奈韦拉平稳态谷浓度，并对部分患者在奈韦拉平给药后1、2和4小时进行额外测量。对奈韦拉平及其五种代谢物的药代动力学进行了表征，并对不同Ishak组的结果进行了比较。在51例肝纤维化患者中，大多数同时感染丙型肝炎病毒或乙型肝炎病毒，观察到的血浆最大浓度与最小浓度之间的差异表明，随着从Ishak第1组进展到Ishak第2组或第3组，全身暴露曲线在统计学上显著变平，提示全身清除率随肝病进展而降低。然而，Ishak组之间的奈韦拉平谷浓度和最大浓度无显著差异。Ishak组之间的代谢物谱也具有可比性。在接受奈韦拉平长期治疗且有不同程度肝纤维化（包括肝硬化）的HIV感染患者中，奈韦拉平血浆谷浓度未显著升高，因此无需调整剂量。
