title: Bilirubin-a potential marker of drug exposure in atazanavir-based antiretroviral therapy.
abstract: The objective of this work was to examine the atazanavir-bilirubin relationship using a population-based approach and to assess the possible application of bilirubin as a readily available marker of atazanavir exposure. A model of atazanavir exposure and its concentration-dependent effect on bilirubin levels was developed based on 200 atazanavir and 361 bilirubin samples from 82 patients receiving atazanavir in the NORTHIV trial. The pharmacokinetics was adequately described by a one-compartment model with first-order absorption and lag-time. The maximum inhibition of bilirubin elimination rate constant (I(max)) was estimated at 91% (95% CI, 87-94) and the atazanavir concentration resulting in half of I(max) (IC50) was 0.30 μmol/L (95% CI, 0.24-0.37). At an atazanavir/ritonavir dose of 300/100 mg given once daily, the bilirubin half-life was on average increased from 1.6 to 8.1 h. A nomogram, which can be used to indicate suboptimal atazanavir exposure and non-adherence, was constructed based on model simulations.
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Sweden. dinko.rekic@gu.se
authors.forename: Dinko
authors.initials: D
authors.lastname: Rekić
authors.forename: Oskar
authors.initials: O
authors.lastname: Clewe
authors.forename: Daniel
authors.initials: D
authors.lastname: Röshammar
authors.forename: Leo
authors.initials: L
authors.lastname: Flamholc
authors.forename: Anders
authors.initials: A
authors.lastname: Sönnerborg
authors.forename: Vidar
authors.initials: V
authors.lastname: Ormaasen
authors.forename: Magnus
authors.initials: M
authors.lastname: Gisslén
authors.forename: Angela
authors.initials: A
authors.lastname: Abelö
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
mesh_terms: D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000097:blood*; D015415:Biomarkers / Q000097:blood*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D001663:Bilirubin