Pharmacokinetics of dolutegravir with and without darunavir/cobicistat

Background: Dolutegravir (DTG) combined with boosted darunavir may be a promising NRTI sparing and/or salvage strategy for the treatment of HIV-1 infection. In patients undergoing drug monitoring, DTG trough concentrations doubled when switching from darunavir/ritonavir (DRV/r) to DRV/cobicistat (c), in contrast to a 38% decrease with darunavir/ritonavir (DRV/r) twice daily. However, no formal interaction studies between DTG and DRV/c have been published. Methods: This phase 1, open label, 57 day, cross over, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65years, who were randomized to: i) group 1: DTG 50mg on days 1-14 followed by a 7 day wash out period, DTG+DRV/c 50mg+800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out, and finally DRV/c 800/150mg on days 43-56 or ii) group 2: DRV/c 800/150mg on days 1-14 followed by a 7 day wash out period, DTG 50mg+DRV/c 800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out and finally DTG 50mg on days 43-56. All doses were administered once daily. Each group underwent intensive PK sampling (0-24 hr post-dose) on days 14, 35 and 56 and DTG/DRV/c concentrations were measured by validated LC-MS methods. Results: To date, 13 healthy volunteers have been screened, 12 baselined and 9 have completed all PK phases (1 subject withdrew for personal reasons and 2 are ongoing). Median age (range) was 31yrs (24-55), 1 was male, 4 self-reported as white and 5 as black African/Caribbean. DTG geometric mean ratios (GMR, DTG+DRV/c versus DTG alone) and 90% confidence intervals (CI) Cmax, AUC, C24h were 0.89 (0.79-1.02), 0.84 (0.73-0.96), 0.81 (0.66-0.98). DRV GMR (DRV/c+DTG versus DRV/c alone, 90%CI) of DRV Cmax, AUC, C24h were 0.79 (0.71-0.89), 0.87 (0.78-0.96), 0.82 (0.67-1.00), and of C Cmax, AUC, C24h were 0.86 (0.77-0.96), 0.88 (0.78-1.00) 0.98 (0.74-1.28), No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusion: Concentrations of DTG during co-administration with DRV/c decreased by <20% and those of DRV with DTG by <21%, suggesting this combination can be prescribed safely in the treatment of HIV-1, including in patients harbouring resistance that benefit from optimal antiretroviral exposures.