ADME 药物遗传学：考察与利托那韦联合应用的抗逆转录病毒药物洛匹那韦的药代动力学。

ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir.

机构信息

Institute of Microbiology, Service of Infectious Diseases, Division of Clinical Pharmacology and Toxicology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.

出版信息

Pharmacogenet Genomics. 2010 Apr;20(4):217-30. doi: 10.1097/FPC.0b013e328336eee4.

DOI:10.1097/FPC.0b013e328336eee4

PMID:20139798

Abstract

BACKGROUND

An ADME (absorption, distribution, metabolism and excretion)-pharmacogenetics association study may identify functional variants relevant to the pharmacokinetics of lopinavir co-formulated with ritonavir (LPV/r), a first-line anti-HIV agent.

METHODS

An extensive search of literature and web resources helped select ADME genes and single nucleotide polymorphisms (SNPs, functional and HapMap tagging SNPs) with a proven or potentially relevant role in LPV/r pharmacokinetics. The study followed a two-stage design. Stage 1 (discovery) considered a Caucasian population (n=638) receiving LPV/r, where we selected 117 individuals with low LPV clearance (cases) and 90 individuals with high clearance (controls). Genotyping was performed by a 1536-SNP customized GoldenGate Illumina BeadArray. Stage 2 (confirmation) represented a replication study of candidate SNPs from the stage 1 in 148 individuals receiving LPV/r. The analysis led to formal population pharmacokinetic-pharmacogenetic modeling of demographic, environmental and candidate SNP effects.

RESULTS

One thousand three hundred and eighty SNPs were successfully genotyped. Nine SNPs prioritized by the stage 1 analysis were brought to replication. Stage 2 confirmed the contribution of two functional SNPs in SLCO1B1, one functional SNP in ABCC2 and a tag SNP of the CYP3A locus in addition to body weight effect and ritonavir coadministration. According to the population pharmacokinetic-pharmacogenetic model, genetic variants explained 5% of LPV variability. Individuals homozygous rs11045819 (SLCO1B14) had a clearance of 12.6 l/h, compared with 5.4 l/h in the reference group, and 3.9 l/h in individuals with two or more variant alleles of rs4149056 (SLCO1B15), rs717620 (ABCC2) or rs6945984 (CYP3A). A subanalysis confirmed that although a significant part of the variance in LPV clearance was attributed to fluctuation in ritonavir levels, genetic variants had an additional effect on LPV clearance.

CONCLUSION

The two-stage strategy successfully identified genetic variants affecting LPV/r pharmacokinetics. Such a general approach of ADME pharmacogenetics should be generalized to other drugs.

摘要

背景

ADME（吸收、分布、代谢和排泄）-药物遗传学关联研究可以识别与洛匹那韦利托那韦（LPV/r）药代动力学相关的功能变异体，LPV/r 是一种一线抗 HIV 药物。

方法

广泛搜索文献和网络资源有助于选择 ADME 基因和单核苷酸多态性（SNP，功能和 HapMap 标记 SNP），这些基因和 SNP 在 LPV/r 药代动力学中具有已证实或潜在相关作用。该研究采用两阶段设计。第一阶段（发现）考虑了接受 LPV/r 的白种人群（n=638），我们从中选择了 117 名 LPV 清除率低的个体（病例）和 90 名清除率高的个体（对照）。基因分型通过 1536-SNP 定制的 GoldenGate Illumina BeadArray 进行。第二阶段（验证）代表了在接受 LPV/r 的 148 名个体中对第一阶段候选 SNP 的复制研究。该分析导致了人口药代动力学-药物遗传学模型的正式建立，该模型考虑了人口统计学、环境和候选 SNP 对体重效应和利托那韦共给药的影响。

结果

成功对 1380 个 SNP 进行了基因分型。第一阶段分析优先考虑的 9 个 SNP 被带到复制阶段。第二阶段证实了 SLCO1B1 中的两个功能 SNP、ABCC2 中的一个功能 SNP 以及 CYP3A 基因座的标签 SNP 的作用，以及体重效应和利托那韦共给药的作用。根据人口药代动力学-药物遗传学模型，遗传变异解释了 LPV 可变性的 5%。SLCO1B14 纯合子 rs11045819 个体的清除率为 12.6 l/h，而参考组为 5.4 l/h，rs4149056（SLCO1B15）、rs717620（ABCC2）或 rs6945984（CYP3A）的两个或更多变异等位基因的个体的清除率为 3.9 l/h。一项亚分析证实，尽管 LPV 清除率的大部分变异归因于利托那韦水平的波动，但遗传变异对 LPV 清除率仍有额外影响。