Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 62; no. 1; p. 21
• Main Authors: Dooley, Kelly E, Sayre, Patrick, Borland, Julie, Purdy, Elizabeth, Chen, Shuguang, Song, Ivy, Peppercorn, Amanda, Everts, Stephanie, Piscitelli, Stephen, Flexner, Charles
• Format: Journal Article
• Language: English
• Published: United States 01.01.2013
• Subjects: Adult; Antitubercular Agents - administration & dosage; Antitubercular Agents - adverse effects; Antitubercular Agents - pharmacokinetics; Cross-Over Studies; Drug Interactions; Female; Heterocyclic Compounds, 3-Ring - administration & dosage; Heterocyclic Compounds, 3-Ring - adverse effects; Heterocyclic Compounds, 3-Ring - pharmacokinetics; HIV Integrase Inhibitors - administration & dosage; HIV Integrase Inhibitors - adverse effects; HIV Integrase Inhibitors - pharmacokinetics; Human Experimentation; Humans; Male; Middle Aged; Rifabutin - administration & dosage; Rifabutin - adverse effects; Rifabutin - pharmacokinetics; Rifampin - administration & dosage; Rifampin - adverse effects; Rifampin - pharmacokinetics
• ISSN: 1944-7884
• DOI: 10.1097/QAI.0b013e318276cda9

Cotreatment of tuberculosis (TB) and HIV among coinfected patients is now the standard of care. Rifampin (RIF) is a standard part of TB treatment but is a potent inducer of drug metabolizing enzymes. This study evaluated the effect of RIF or rifabutin (RBT) on the pharmacokinetics of the investigational HIV integrase inhibitor, dolutegravir (DTG). Phase I pharmacokinetic drug interaction study. In arm 1, healthy subjects received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily together with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg of DTG once daily together with 300 mg of RBT once daily for 14 days (period 2). PK sampling was performed at the end of each period. In arm 1, comparing period 3 to period 1, the geometric mean ratio (GMR) for the 24-hour area under the time-concentration curve (AUC0-24) was 1.33 [90% confidence interval (CI): 1.14 to 1.53], and the GMR for the trough (Cτ) was 1.22 (90% CI: 1.01 to 1.48). Comparing period 2 to period 1 in arm 2, the GMR for the AUC0-24 was 0.95 (90% CI: 0.82 to 1.10), and the GMR for the Cτ was 0.70 (90% CI: 0.57 to 0.87). Regimens including twice-daily DTG and RIF or once-daily DTG and RBT may represent a new treatment option for patients who require concomitant treatment of HIV and TB.