Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose

Abstract

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. 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, co-administration of UGT1A1 inhibitors may increase the plasma levels of q.d. 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/m . Subjects (n = 14) received a single oral dose of 1200 mg raltegravir in period 1. After a washout period of at least 7 days, the subjects received oral doses of 400 mg atazanavir q.d. 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 h following raltegravir dosing and analysed using a validated bioanalytical method to quantify raltegravir plasma concentrations. Co-administration with atazanavir yielded GMRs (90% CIs) for raltegravir AUC , C and C 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 the mean bilirubin by up to 200%, an effect that was preserved in the atazanavir/raltegravir treatment group. Administration of single q.d. 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, co-administration of atazanavir with raltegravir q.d. is not recommended. Copyright © 2016 John Wiley & Sons, Ltd.

A population pharmacokinetics analysis assessing the exposure of raltegravir once‐daily 1200 mg in pregnant women living with HIV

“…Data from 11 pharmacokinetic studies with raltegravir and rich sampling schedules were pooled 8,10,14–21 . These studies include a combination of healthy and HIV‐infected subjects taking 400 mg and 600 mg raltegravir tablets, and pregnant subjects taking the 400 mg tablets.…”

“…These studies include a combination of healthy and HIV‐infected subjects taking 400 mg and 600 mg raltegravir tablets, and pregnant subjects taking the 400 mg tablets. The study protocols and subject characteristics are summarized in Table 1, and detailed information can be found in the original publications 8,10,14–21 . Twenty‐two European, HIV‐infected, pregnant women treated with a 400 mg b.i.d.…”

“…Sex was tested as covariate on F, and White ethnicity as covariate on central volume of distribution (Vc) 24 . We tested atazanavir and efavirenz co‐administration as covariates on F and CL 19,20,32 . Pregnancy was tested as a dichotomous covariate on CL, mean absorption time (MAT), F, Vc, and absorption rate (Ka) 3 .…”

“…Data from 11 pharmacokinetic studies with raltegravir and rich sampling schedules were pooled. 8,10,[14][15][16][17][18][19][20][21] These studies include a combination of healthy and HIV-infected subjects taking 400 mg and 600 mg raltegravir tablets, and pregnant subjects taking the 400 mg tablets. The study protocols and subject characteristics are summarized in Table 1, and detailed information can be found in the original publications.…”

“…The study protocols and subject characteristics are summarized in Table 1, and detailed information can be found in the original publications. 8,10,[14][15][16][17][18][19][20][21] Twenty-two European, HIVinfected, pregnant women treated with a 400 mg b.i.d. raltegravir-based regimen were included to determine the effect of pregnancy on the pharmacokinetics of raltegravir.…”