title: External validation of the bilirubin-atazanavir nomogram for assessment of atazanavir plasma exposure in HIV-1-infected patients.
abstract: Atazanavir increases plasma bilirubin levels in a concentration-dependent manner. Due to less costly and readily available assays, bilirubin has been proposed as a marker of atazanavir exposure. In this work, a previously developed nomogram for detection of suboptimal atazanavir exposure is validated against external patient populations. The bilirubin nomogram was validated against 311 matching bilirubin and atazanavir samples from 166 HIV-1-infected Norwegian, French, and Italian patients on a ritonavir-boosted regimen. In addition, the nomogram was evaluated in 56 Italian patients on an unboosted regimen. The predictive properties of the nomogram were validated against observed atazanavir plasma concentrations. The use of the nomogram to detect non-adherence was also investigated by simulation. The bilirubin nomogram predicted suboptimal exposure in the patient populations on a ritonavir-boosted regimen with a negative predictive value of 97% (95% CI 95-100). The bilirubin nomogram and monitoring of atazanavir concentrations had similar predictive properties for detecting non-adherence based on simulations. Although both methods performed adequately during a period of non-adherence, they had lower predictive power to detect past non-adherence episodes. Using the bilirubin nomogram for detection of suboptimal atazanavir exposure in patients on a ritonavir-boosted regimen is a rapid and cost-effective alternative to routine measurements of the actual atazanavir exposure in plasma. Its application may be useful in clinical settings if atazanavir concentrations are not available.
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. dinko.rekic@gu.se
authors.forename: Dinko
authors.initials: D
authors.lastname: Rekić
authors.forename: Daniel
authors.initials: D
authors.lastname: Röshammar
authors.forename: Martin
authors.initials: M
authors.lastname: Bergstrand
authors.forename: Joel
authors.initials: J
authors.lastname: Tarning
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.forename: Vidar
authors.initials: V
authors.lastname: Ormaasen
authors.forename: Marie
authors.initials: M
authors.lastname: Vigan
authors.forename: Aurélie
authors.initials: A
authors.lastname: Barrail-Tran
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
authors.forename: Magnus
authors.initials: M
authors.lastname: Gisslén
authors.forename: Angela
authors.initials: A
authors.lastname: Äbelö
mesh_terms: D000328:Adult; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D003198:Computer Simulation; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D049451:Nomograms; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D019438:Ritonavir / Q000008:administration & dosage
chemical_list: D015415:Biomarkers; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir; D001663:Bilirubin