同时基于药物遗传学的达若那韦和利托那韦在hiv感染患者中的人群药代动力学分析

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Molto J, Xinarianos G, Miranda C, Pushpakom S, Cedeno S, Clotet B, Owen A, Valle M

同时基于药物遗传学的达若那韦和利托那韦在hiv感染患者中的人群药代动力学分析

临床药典，2013 july;52(7):543-53。doi: 10.1007 / s40262 - 013 - 0057 - 6。

PubMed ID

23494984 (PubMed视图

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摘要

背景:Darunavir是一种有效的HIV蛋白酶抑制剂。为了增强其药代动力学特征，达若那韦必须与利托那韦联合使用。然而，在hiv感染个体中，达若那韦药代动力学存在广泛的患者间差异。Darunavir是一种已知的内流转运蛋白底物，如溶质载体有机阴离子转运蛋白家族(SLCO1A2, SLCO1B1)的1A2和1B1成员，以及多药耐药蛋白1 (MRP1)等外排转运蛋白底物。目的:本研究的目的是建立达若那韦和利托那韦在hiv感染成人中的半机械人群药代动力学模型。所期望的模型将纳入患者特征和药物遗传学数据，有助于药物浓度的变异性，并考虑到两种化合物之间的相互作用。方法:对75名接受达那韦/利托那韦(600/100 mg，每日2次)至少4周的白种人705份血浆样本进行人群药代动力学分析。每个参与者至少获得一个完整的药代动力学剖面，并通过高效液相色谱法测定血浆中达若那韦和利托那韦的浓度。通过MALDI-TOF质谱和基于实时聚合酶链反应的等位基因鉴别两种方法，对148个转运蛋白或代谢酶编码基因多态性进行了基因分型。建立了达若那韦和利托那韦的种群药代动力学模型。 The effect of single nucleotide polymorphisms on the post hoc individual pharmacokinetic parameters was first explored using graphic methods and regression analysis. Those covariates related to changes in darunavir or ritonavir pharmacokinetic parameters were then further evaluated using non-linear mixed effects modeling (NONMEM version VII). RESULTS: Darunavir and ritonavir pharmacokinetics were best described by a two- and one-compartment model, respectively, both with first-order absorption and elimination. The darunavir peripheral volume of distribution decreased as alpha1-acid glycoprotein concentrations increased. Darunavir clearance was 12 % lower in patients with SLCO3A1 rs8027174 GT/TT genotypes, while homozygosity for the rs4294800 A allele was associated with 2.5-fold higher central volume of distribution. Body weight influenced ritonavir clearance. Ritonavir inhibited darunavir clearance following a maximum-effect model. CONCLUSION: A population pharmacokinetic model to simultaneously describe the pharmacokinetics of darunavir and ritonavir was developed in HIV-infected patients. The model provides better understanding of the interaction between darunavir and ritonavir and suggests an association between SLCO3A1 polymorphisms and darunavir pharmacokinetics. Bayesian estimates of individual darunavir parameters and ritonavir may be useful to predict darunavir exposure.

引用本文的药物库数据

药物转运蛋白

药物	转运体	种类	生物	药理作用	行动
内	溶质载体有机阴离子转运体家族成员1B1	蛋白质	人类	未知的	抑制剂	细节