Dolutegravir does not affect methadone pharmacokinetics in opioid-dependent, HIV-seronegative subjects.

Abstract

Dolutegravir (DTG) is an investigational integrase inhibitor for treatment of HIV infection. As intravenous drug use is a common risk factor for HIV, this study evaluated the effect of DTG on the pharmacokinetics (PK) of methadone. This was an open-label, 2-period study in adult, opioid-dependent, HIV-seronegative subjects. Subjects received their current individual methadone doses once daily for 3 days (Period 1) followed by DTG 50mg twice daily (BID) for 5 days while continuing their stable methadone therapy (Period 2). Serial PK samples for R- and S-methadone were collected after each Period. Pharmacodynamic (PD) measures and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated. Plasma exposures of total, R-, and S-methadone were not affected by co-administration of DTG. Mean ratios for AUC were 0.98, 0.95, and 1.01 for total, R-, and S-methadone, respectively, alone compared with in combination with DTG. No statistically significant differences were noted between the 2 treatment periods in methadone PD measures. The combination of DTG and methadone was well tolerated. No deaths, serious adverse events, or grade 3/4 adverse events occurred. No clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Co-administration of methadone with repeat doses of DTG 50mg BID had no effect on total, R-, and S-methadone PK or on methadone-induced PD markers. No dose adjustment in methadone is required when given in combination with DTG.