Safety, Tolerability, and Pharmacokinetics of the HIV Integrase Inhibitor Dolutegravir Given Twice Daily with Rifampin: Results of a Phase I Study among Healthy Subjects
Kelly Dooley*1, E Purdy1, P Sayre1, J Borland2, S Chen2, I Song2, A Peppercorn2, S Everts1, S Piscitelli2, and C Flexner1
1Johns Hopkins Univ Sch of Med, Baltimore, MD, US and 2GlaxoSmithKline, Res Triangle Park, NC, US
Background: Dolutegravir (DTG) is an investigational HIV integrase inhibitor currently in Phase 3 trials. Tuberculosis (TB) is the leading cause of death in HIV-infected patients, and TB and HIV must often be treated concomitantly. Rifampin, the key sterilizing drug in TB regimens, induces drug metabolizing enzymes, leading to reductions in concentrations of most co-administered antiretrovirals. DTG is primarily metabolized by UGT1A1 with CYP3A4 as a minor route, and both enzymes are induced by rifampin. Increasing the DTG dose could overcome the anticipated effects of rifampin on DTG concentrations.
Methods: Phase I open-label, three-period, fixed-sequence, single center pharmacokinetic (PK) drug interaction study. Healthy HIV-seronegative subjects received DTG 50 mg once daily for 7 days (period 1), then DTG 50 mg twice daily for 7 days (period 2), then DTG 50 mg twice daily together with rifampin 600 mg once daily (period 3) for 14 days. Plasma PK sampling was performed at the end of each dosing period. Concentrations of DTG were determined using LC-MS/MS. Non-compartmental PK analysis was performed; geometric least squares mean ratios (GMR) and 90% confidence intervals (CI) were generated for treatment comparison.
Results: Twelve subjects were enrolled and 11 completed all PK sampling periods. Median age was 49 years, median weight was 79 kg, 67% were African-American, and 17% were women. Twice daily DTG plus rifampin achieved mean PK parameters that were 20-33% higher than once daily dosing alone. Comparing period 3 (DTG twice daily plus rifampin) to period 1 (DTG once daily), the GMR for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 (90% CI 1.14 to 1.54), and the GMR for the trough at the end of the dosing interval (Cτ) was 1.22 (90% CI 1.01 to 1.47). There were no discontinuations for adverse events (AEs) and no Grade 3 or higher AEs. One subject experienced grade 2 lymphopenia at the end of period 3 and self-limited rash after completing study drugs.
Conclusions: DTG at 50 mg twice daily given together with standard-dose rifampin was well-tolerated and resulted in DTG concentrations similar to those of DTG 50 mg given once-daily alone. Regimens including twice-daily DTG may represent a new treatment option for patients who require concomitant treatment of HIV and TB.