洛匹那韦/利托那韦在未合并肝功能损害的HIV和丙型肝炎病毒合并感染患者中的药代动力学：肝纤维化的影响

Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment: influence of liver fibrosis.

作者信息

Moltó José, Valle Marta, Blanco Asunción, Negredo Eugenia, DelaVarga Meritxell, Miranda Cristina, Miranda José, Domingo Pere, Vilaró Josep, Tural Cristina, Costa Joan, Barbanoj Manuel José, Clotet Bonaventura

机构信息

Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.

出版信息

Clin Pharmacokinet. 2007;46(1):85-92. doi: 10.2165/00003088-200746010-00005.

DOI:10.2165/00003088-200746010-00005

PMID:17201460

Abstract

BACKGROUND AND OBJECTIVE

To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment.

METHODS

Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach.

RESULTS

Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively).

CONCLUSION

Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

摘要

背景与目的

评估丙型肝炎病毒（HCV）合并感染及肝纤维化程度对未出现肝功能损害的HIV感染患者洛匹那韦/利托那韦药代动力学的影响。

方法

一项横断面比较研究，纳入接受洛匹那韦/利托那韦（400毫克/100毫克，每日两次）治疗的HIV感染成人。根据FIB-4指数，将HIV/HCV合并感染患者分为有进展性纤维化（HCV+/FIB+，n = 7）和无进展性纤维化（HCV+/FIB-，n = 8）两组。为每位患者获取完整的浓度-时间曲线，并在洛匹那韦/利托那韦给药前（0小时）以及给药后1、2、4、6、8、10和12小时采集血样。采用高效液相色谱法测定血浆中洛匹那韦和利托那韦的浓度。使用非房室模型方法为每位个体计算最大和最小血浆浓度（Cmax和Cmin）、0至12小时血浆浓度-时间曲线下面积（AUC12）、稳态时表观口服清除率（CLss/F）以及口服给药后的表观分布容积（Vd/F）。

结果

共纳入26例HCV阴性和22例HCV阳性患者。HCV阴性和HCV阳性患者之间洛匹那韦和利托那韦的药代动力学具有可比性。然而，HCV+/FIB+患者中洛匹那韦的Vd/F比HCV阴性患者高125%（p = 0.015），比HCV+/FIB-患者高107%（p = 0.040）。HCV+/FIB+患者中利托那韦的CLss/F比HCV阴性患者低40%（p = 0.005），比HCV+/FIB-患者低44%（p = 0.040）。因此，对于利托那韦，HCV+/FIB+患者的AUC12、Cmax和Cmin分别比HCV阴性患者的这些参数高63%、86%和100%（分别为p = 0.005、p = 0.012和p = 0.015），比HCV+/FIB-患者的水平分别高80%、86%和100%（分别为p = 0.040、p = 0.040和p = 0.029）。