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

Lubomirov, Rubin and di Iulio, Julia and Fayet, Aurélie and Colombo, Sara and Martinez, Raquel and Marzolini, Catia and Furrer, Hansjakob and Vernazza, Pietro and Calmy, Alexandra and Cavassini, Matthias and Ledergerber, Bruno and Rentsch, Katharina and Descombes, Patrick and Buclin, Thierry and Decosterd, Laurent A. and Csajka, Chantal and Telenti, Amalio and Swiss HIV Cohort Study, . (2010) ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir. Pharmacogenetics and Genomics, 20 (4). pp. 217-230.

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Official URL: https://edoc.unibas.ch/69528/

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Abstract

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.; 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.; 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.; 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Infektiologie > Infektiologie (Battegay M)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Infektiologie > Infektiologie (Battegay M)
UniBasel Contributors:Marzolini, Catia
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Lippincott Williams & Wilkins
ISSN:1744-6872
e-ISSN:1744-6880
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Jul 2020 13:25
Deposited On:01 Jul 2020 13:25

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