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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Lubomirov Rubin, di Iulio Julia, Fayet Aurélie, Colombo Sara, Martinez Raquel, Marzolini Catia, Furrer Hansjakob, Vernazza Pietro, Calmy Alexandra, Cavassini Matthias, Ledergerber Bruno, Rentsch Katharina, Descombes Patrick, Buclin Thierry, Decosterd Laurent A, Csajka Chantal, Telenti Amalio, Swiss HIV Cohort Study,
Project Pharmacocinétique de population, pharmacogénétique, et profils métaboliques de la thérapie anti-HIV
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Original article (peer-reviewed)

Journal Pharmacogenetics and genomics
Volume (Issue) 20(4)
Page(s) 217 - 30
Title of proceedings Pharmacogenetics and genomics
DOI 10.1097/FPC.0b013e328336eee4

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 (SLCO1B1*4) 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 (SLCO1B1*5), 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.
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