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


CONCLUSIONS
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.
Institute of Microbiology, Service of Infectious Diseases, Division of Clinical Pharmacology and Toxicology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
Rubin
R
Lubomirov
Julia
J
di Iulio
Aurélie
A
Fayet
Sara
S
Colombo
Raquel
R
Martinez
Catia
C
Marzolini
Hansjakob
H
Furrer
Pietro
P
Vernazza
Alexandra
A
Calmy
Matthias
M
Cavassini
Bruno
B
Ledergerber
Katharina
K
Rentsch
Patrick
P
Descombes
Thierry
T
Buclin
Laurent A
LA
Decosterd
Chantal
C
Csajka
Amalio
A
Telenti
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001682:Biological Availability; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
D019380:Anti-HIV Agents; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D027381:Liver-Specific Organic Anion Transporter 1; D061466:Lopinavir; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D011744:Pyrimidinones; D019438:Ritonavir; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C104464:CYP3A protein, human