title: A population pharmacokinetic-pharmacogenetic analysis of atazanavir.
abstract: Atazanavir is a first-line HIV protease inhibitor commonly co-dosed with ritonavir. Ritonavir inhibits atazanavir metabolism, decreasing variability and increasing plasma concentrations. However, ritonavir use results in higher costs and increased drug-related adverse events. Elucidating atazanavir pharmacokinetics might allow for individualized ritonavir boosting. We previously demonstrated that genetically determined CYP3A5 nonexpression was associated with slower atazanavir clearance CL/F and higher trough concentrations. This effect was prominent in non-African-American men but absent in African-Americans. The present study considers additional genetic predictors of atazanavir CL/F with a focus on race differences. Nine polymorphisms in CYP3A4, ABCG2, NR1I2 (PXR), and SLCO1B1 were evaluated; 330 plasma samples from 30 HIV-negative volunteers, balanced by sex, race, and CYP3A5 expressor status, were available. Analyses were performed using nonlinear mixed-effects modeling (NONMEM). The following factors were univariately associated with atazanavir CL/F (% effect) : African-American race (decreased 35%), female sex (decreased 25%), older age (decreased 1.7%/year), CYP3A5 nonexpressors (decreased 26%), ABCB1 CGC haplotype carriers (1236C/2677G/3435C) (decreased 33%), and CYP3A4*1B carriers (decreased 31%). However, an independent genetic explanation for the differential race effect could not be identified. An interaction was observed with PXR 63396 C>T and CYP3A5 expressor status (p=0.0002). CYP3A5 nonexpressors with a PXR 63396 CC genotype had 37% slower CL/F versus those with CT or TT genotypes. For CYP3A5 expressors, those with a PXR 63396 CC genotype had 63% faster CL/F versus those with CT or TT genotypes. Although this study has as its main limitation a small overall sample size, these results nonetheless provide new leads and impetus to evaluate ways to individualize the need for ritonavir boosting using demographic and genetic predictors of atazanavir pharmacokinetics.
authors.affiliation: Colorado Health Outcomes Program, University of Colorado Denver School of Medicine, Aurora, USA.
authors.forename: Deidre A
authors.initials: DA
authors.lastname: Kile
authors.forename: Samantha
authors.initials: S
authors.lastname: MaWhinney
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rower
authors.forename: Jose R
authors.initials: JR
authors.lastname: Castillo-Mancilla
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000069446:Atazanavir Sulfate; D003362:Cost-Benefit Analysis; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006239:Haplotypes / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir