title: Pharmacokinetic-pharmacodynamic modeling of unboosted Atazanavir in a cohort of stable HIV-infected patients.
abstract: Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h(-1); P = 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC(0-24)], 10.3 ± 2.1 versus 22.4 ± 11.2 mg · h · liter(-1); P = 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.
authors.affiliation: Service Pharmaceutique-Groupement Hospitalier de Gériatrie, Lyon, France. sylvain.goutelle@chu-lyon.fr
authors.forename: Sylvain
authors.initials: S
authors.lastname: Goutelle
authors.forename: Thomas
authors.initials: T
authors.lastname: Baudry
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gagnieu
authors.forename: André
authors.initials: A
authors.lastname: Boibieux
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Livrozet
authors.forename: Dominique
authors.initials: D
authors.lastname: Peyramond
authors.forename: Christian
authors.initials: C
authors.lastname: Chidiac
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.forename: Tristan
authors.initials: T
authors.lastname: Ferry
mesh_terms: D000328:Adult; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D001682:Biological Availability; D004334:Drug Administration Schedule; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000254:growth & development; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D017211:Treatment Failure
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate