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.
BACKGROUND
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).


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. kdooley1@jhmi.edu
Kelly E
KE
Dooley
Patrick
P
Sayre
Julie
J
Borland
Elizabeth
E
Purdy
Shuguang
S
Chen
Ivy
I
Song
Amanda
A
Peppercorn
Stephanie
S
Everts
Stephen
S
Piscitelli
Charles
C
Flexner
D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006805:Human Experimentation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D017828:Rifabutin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000099226:Dolutegravir
D000995:Antitubercular Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D017828:Rifabutin; D012293:Rifampin; D000099226:Dolutegravir