Pharmacokinetics of Raltegravir in HIV-Infected Patients on Rifampicin-Based Antitubercular Therapy

Background. Rifampicin (RIF) induces UGT1A1, an enzyme involved in raltegravir (RAL) elimination, thereby potentially lowering RAL exposure. We examined the pharmacokinetics of RAL in human immunodeficiency virus (HIV)-infected patients on RIF-based antitubercular therapy in the French National Agency for HIV/AIDS and Viral Hepatitis Research 12 180 Reflate Tuberculosis trial. Methods. Patients started RAL in combination with tenofovir disoproxil fumarate and lamivudine after initiation of RIF (10 mg/kg/day). In arm 1 (n = 21), they received 400 mg RAL twice daily; in arm 2 (n = 16), they received RAL 800 mg twice daily initially then 400 mg twice daily 4 weeks after RIF discontinuation. Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of RAL together with RIF (period 1), 4 weeks after RIF discontinuation (period 2), and after the RAL dose reduction in arm 2 (period 3). Results. In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval [CI],.64-1.37) for the 12-hour area under the time-concentration curve (AUC(0-12)), and 0.69 (90% CI,.42-1.13) for the concentration at 12 hours (C-12). In arm 2, the corresponding GMRs were 0.75 (90% CI,.48-1.17) and 1.10 (90% CI,.61-2.00) for period 1 vs period 2, and 1.10 (90% CI,.78-1.55) and 1.68 (90% CI,.88-3.23) for period 1 vs period 3. Conclusions. The double dose of RAL overcompensated for RIF induction, but the standard dose was associated with only small decreases in AUC(0-12) and C12 during RIF coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection.