title: Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients.
abstract: We investigated population pharmacokinetics and pharmacogenetics of ritonavir-boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, INSERM, UMR, France. rada.savic@ucsf.edu
authors.forename: R M
authors.initials: RM
authors.lastname: Savic
authors.forename: A
authors.initials: A
authors.lastname: Barrail-Tran
authors.forename: X
authors.initials: X
authors.lastname: Duval
authors.forename: G
authors.initials: G
authors.lastname: Nembot
authors.forename: X
authors.initials: X
authors.lastname: Panhard
authors.forename: D
authors.initials: D
authors.lastname: Descamps
authors.forename: C
authors.initials: C
authors.lastname: Verstuyft
authors.forename: B
authors.initials: B
authors.lastname: Vrijens
authors.forename: A-M
authors.initials: AM
authors.lastname: Taburet
authors.forename: C
authors.initials: C
authors.lastname: Goujard
authors.forename: F
authors.initials: F
authors.lastname: Mentré
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000483:Alleles; D000069446:Atazanavir Sulfate; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use; D010597:Pharmacogenetics; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D000068698:Tenofovir; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D063065:Organophosphonates; D011725:Pyridines; D003841:Deoxycytidine; D000069446:Atazanavir Sulfate; D000068698:Tenofovir; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D000068679:Emtricitabine; D000225:Adenine; D019438:Ritonavir