Extended mathematical model for "in vivo" quantification of the interaction betweeen atazanavir and bilirubin.
The objective of the present work was to conduct an "in vivo" analysis of the atazanavir-bilirubin interaction. We developed a new mathematical approach to PK/PDPK models for competitive interaction based on the Michaelis-Menten equation, which was applied to patients with polymorphisms in the gene for UDP-glucuronosyltransferase 1A1 (UGT1A1). Atazanavir is known to induce concentration-dependent increases in bilirubin plasma levels. Thus, we employed our mathematical model to analyse rises in steady state atazanavir and bilirubin concentrations, ultimately plotting a nomogram for detection of suboptimal atazanavir exposure. Application of our model revealed that an absolute value or a steady state increase in bilirubin falling below 3.8Φ µmol/L (where Φ is a correction factor, =1 for UGT1A1 wild type and ≠1 for UGT1A1 variants) could be used to predict suboptimal atazanavir exposure and treatment failure. Thus, we have successfully established a new mathematical approach for pharmacodynamic-pharmacokinetic modelling of the interaction between atazanavir and bilirubin, as it relates to genetic variants of UGT1A1. Taken together, our findings indicate that bilirubin plasma levels represent a valuable marker of atazanavir exposure.
Department of Pharmacy, Hospital Real Ntra. Sra. de Gracia, Zaragoza, Spain.
Roberto
R
Lozano
Nieves
N
Domeque
Alberto-Fermín
AF
Apesteguia
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000097:blood*; D054316:Biomarkers, Pharmacological / Q000097:blood; D004359:Drug Therapy, Combination / Q000706:statistics & numerical data; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D009842:Oligopeptides / Q000097:blood / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult; D000099148:UGT1A1 Enzyme
D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D001663:Bilirubin; D054316:Biomarkers, Pharmacological; D014453:Glucuronosyltransferase; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000099148:UGT1A1 Enzyme
HIV; atazanavir; bilirubin; drug interaction; pharmacodynamic model; pharmacokinetic model