Lack of a Clinically Meaningful Pharmacokinetic Effect of Rifabutin on Raltegravir: In Vitro/In Vivo Correlation

Abstract

Raltegravir is an HIV-1 integrase strand transfer inhibitor with potent activity against HIV-1. A prior investigation of raltegravir coadministered with rifampin demonstrated a decrease in plasma concentrations of raltegravir likely secondary to induction of UGT1A1, the enzyme primarily responsible for the metabolism of raltegravir. Little is known regarding the induction of UGT1A1 by rifabutin, an alternate rifamycin. In vitro characterization of the induction potency of rifampin and rifabutin on UGT1A1 was performed. In vitro studies indicate that rifabutin is a less potent inducer of UGT1A1 messenger RNA expression than is rifampin. A fixed-sequence, 2-period, clinical crossover study was conducted to assess the effect of rifabutin on plasma levels of raltegravir: period 1, 400 mg of raltegravir every 12 hours for 4 days; period 2, 400 mg of raltegravir every 12 hours and 300 mg of rifabutin once daily for 14 days. Geometric mean ratio (GMR) (coadministration of rifabutin and raltegravir vs raltegravir alone) of raltegravir area under the concentration-time curve from 0 to 12 hours post dose (AUC(0-12h)) and the 90% confidence interval (CI) was 1.19 (0.86-1.63); GMR of concentration at 12 hours (C(12h)) and 90% CI was 0.80 (0.68-0.94); and GMR of time to maximal concentration (C(max)) and 90% CI was 1.39 (0.87-2.21). Overall, coadministration of rifabutin did not alter raltegravir pharmacokinetics to a clinically meaningful degree.

HIV and Tuberculosis: a Deadly Human Syndemic

“…If coadministered with rifampin, the dose of raltegravir or maraviroc must be increased (85,258). Rifabutin has less of an effect on raltegravir metabolism and may be more appropriate for coadministration (30).…”

Update on Opportunistic Infections in the Era of Effective Antiretroviral Therapy

“…41 In healthy, HIV-negative volunteers, co-administration of rifabutin did not have a clinically meaningful effect on raltegravir pharmacokinetics. 42 Twice-daily dolutegravir with rifampin or once-daily dolutegravir with rifabutin appear to provide acceptable drug levels. 43 Although promising, more data is needed on the efficacy and toxicity of co-administration of HIV integrase inhibitors with TB therapy…”

British HIV Association guidelines for the treatment of TB/HIV coinfection 2011

“…The data regarding interactions with rifabutin suggest normal doses of raltegravir and rifabutin can be used [110]. …”