Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (BID). Raltegravir 1200 mg once-daily (QD) [investigational QD formulation of 2 x 600 mg tablets; QD RAL] was found to be generally well tolerated and non-inferior to the marketed 400 mg BID dose at 48 weeks in a Phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, coadministration of UGT1A1 inhibitors may increase plasma levels of QD RAL. To assess this potential, the drug interaction of 1200 mg raltegravir using atazanavir, a known UGT1A1 inhibitor, was studied. An open-label, randomized, 2-period, fixed-sequence Phase 1 study was performed in adult healthy male and female (non-childbearing potential) subjects ≥ 19 and ≤ 55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2. Subjects (n = 14) received a single oral dose of 1200 mg raltegravir in Period 1. After a washout period of at least 7 days, subjects received oral doses of 400 mg atazanavir QD for 9 consecutive days, with a single oral dose of 1200 mg raltegravir co-administered on Day 7 of Period 2. Serial blood samples were collected for 72 hours following raltegravir dosing and analyzed using a validated bioanalytical method to quantify raltegravir plasma concentrations. Co-administration with atazanavir yielded GMRs (90% CIs) for raltegravir AUC0-∞, Cmax, and C24 of 1.67 (1.34, 2.10), 1.16 (1.01, 1.33), and 1.26 (1.08, 1.46), respectively. There was no effect of raltegravir on serum total bilirubin. In contrast, atazanavir increased mean bilirubin by up to 200%, an effect that was preserved in the atazanavir/raltegravir treatment group. Administration of single QD RAL alone and co-administered with multiple oral doses of atazanavir were generally well tolerated in healthy subjects. The results show that atazanavir increased the PK exposure of raltegravir; therefore, coadministration of atazanavir with raltegravir QD is not recommended.