ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir.
Details
Serval ID
serval:BIB_F0BE883DE124
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir.
Journal
Pharmacogenetics and Genomics
Working group(s)
Swiss HIV Cohort Study
Contributor(s)
Battegay M., Bernasconi E., Böni J., Bucher HC., Bürgisser P., Calmy A., Cattacin S., Cavassini M., Dubs R., Egger M., Elzi L., Fischer M., Flepp M., Fontana A., Francioli P., Furrer H., Fux CA., Gorgievski M., Günthard HF., Hirsch HH., Hirschel B., Hösli I., Kahlert C., Kaiser L., Karrer U., Kind C., Klimkait T., Ledergerber B., Martinetti G., Müller N., Nadal D., Paccaud F., Pantaleo G., Rauch A., Regenass S., Rickenbach M., Rudin C., Schmid P., Schultze D., Schüpbach J., Speck R., de Tejada BM, Taffé P., Telenti A., Trkola A., Vernazza P., Weber R., Yerly S.
ISSN
1744-6880 (Electronic)
ISSN-L
1744-6872
Publication state
Published
Issued date
2010
Volume
20
Number
4
Pages
217-230
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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.
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.
Keywords
Adult, Aged, Aged, 80 and over, Alleles, Anti-HIV Agents/administration & dosage, Anti-HIV Agents/pharmacokinetics, Biological Availability, Cohort Studies, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System/genetics, Female, Genetic Association Studies, Genetic Variation, Humans, Lopinavir, Male, Middle Aged, Models, Genetic, Multidrug Resistance-Associated Proteins/genetics, Organic Anion Transporters/genetics, Pharmacogenetics, Polymorphism, Single Nucleotide, Pyrimidinones/administration & dosage, Pyrimidinones/pharmacokinetics, Ritonavir/administration & dosage, Ritonavir/pharmacokinetics, Young Adult
Pubmed
Web of science
Create date
27/04/2010 12:02
Last modification date
06/08/2024 6:02
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