Population Pharmacodynamic Assessment of Atazanavir Exposure, Uridine Diphosphate-Glucuronosyl Transferase (UGT) 1A1 Genotype and Safety in Healthy Subjects

Authors: O’Mara E, Randall D, Passarell JA, Steinberg S, Ludwig E, Grasela D, Cirincione B
Conference: ICAAC
Keywords: anti-infectives, bilirubin, genotypes, HIV, infectious disease, Kruskal-Wallis, logistic regression, oral, PD, pharmacodynamic, protease inhibitor, safety, steady state, transferase, trend analysis, UGT, uridine, Wilcoxon
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Background: Atazanavir (BMS-232632) is a potent HIV-protease inhibitor with a favorable resistance profile in vitro. Dose-related elevations of total bilirubin (primarily unconjugated) have been observed with atazanavir, and are attributed to  inhibition of UGT 1A1, which glucuronidates unconjugated bilirubin. Total bilirubin levels observed secondary to isoform inhibition by atazanavir are not considered clinically toxic. The two principal alleles in the promoter region of the UGT 1A1 gene are designated “6” and “7.” The 7/7 genotype is synonymous with Gilbert’s syndrome.

Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Diego, California, September 2002

By O’Mara E, Randall D, Julie Passarell, Steinberg S, Elizabeth Ludwig, Grasela D, Cirincione B