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.
Lubomirov
Rubin
R
Institute of Microbiology, Service of Infectious Diseases, Division of Clinical Pharmacology and Toxicology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
di Iulio
Julia
J
Fayet
Aurélie
A
Colombo
Sara
S
Martinez
Raquel
R
Marzolini
Catia
C
Furrer
Hansjakob
H
Vernazza
Pietro
P
Calmy
Alexandra
A
Cavassini
Matthias
M
Ledergerber
Bruno
B
Rentsch
Katharina
K
Descombes
Patrick
P
Buclin
Thierry
T
Decosterd
Laurent A
LA
Csajka
Chantal
C
Telenti
Amalio
A
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