Background
Tuberculosis (TB) causes 25% of all deaths among HIV-infected individuals. Rifampicin (RIF) is a potent inducer of drug metabolising enzymes and drug transporters and co-administration with dolutegravir (DTG) reduces DTG exposure, which can be overcome by doubling the DTG dose to 50 mg twice-daily. We investigated the effect of RIF on the DTG exposure when dosed at 100 mg once-daily, which could provide an easier option than 50 mg twice-daily.

Methods
We conducted an open label, pharmacokinetic (PK) study. Healthy HIV-negative subjects received DTG 50 mg for seven days (PK1), DTG 100 mg for seven days (PK2), RIF only for 14 days, DTG 50 mg plus RIF for seven days (PK3), and DTG 100 mg plus RIF for seven days (PK4). Steady state full DTG PK profiles were evaluated.

Results
DTG geometric mean ratios (GMR) (90% confidence intervals, CI) of PK3/PK1 of 50 mg Cmax, AUC24h, and C24h were 0.65 (0.55-0.75), 0.44 (0.37-0.52), 0.15 (0.13-0.17). GMR (90% CI) of PK4/PK1 Cmax, AUC24h, and C24h were 1.09 (0.97-1.21), 0.74 (0.64-0.86), 0.24 (0.20-0.28). C24h median (range) of DTG 50 mg plus RIF and DTG 100 mg plus RIF were 251(129–706) ng/mL and 140 (73-426) ng/mL, respectively.

Conclusion
Although there were substantial reductions in DTG C24h when co-administered with RIF, concentrations of both DTG 50 mg and 100 mg once-daily with RIF were still above the protein binding-adjusted IC90 of 64 ng/mL. Further studies in HIV-TB co-infected individuals are warranted to confirm these results.

Clinical trial registration number (NCT03199690)