Background:  Dolutegravir (DTG) is an unboosted, HIV integrase inhibitor with a predictable pharmacokinetic profile and activity against viruses resistant to raltegravir that is currently in phase 3 clinical trials. DTG is primarily metabolized by UGT1A1 with CYP3A4 as a minor route, thus hepatic impairment has the potential to affect DTG exposure.

Methods:  The effect of moderate hepatic impairment on DTG pharmacokinetics was evaluated in a single-dose, open-label, parallel group study. We enrolled 8 adult males and females with moderate hepatic impairment as determined by Child-Pugh classification score of 7-9 (Class B) and 8 matched healthy control subjects with normal hepatic function. Control subjects were matched for gender, age, and body mass index. Subjects received DTG 50 mg as a single dose in the fasted state followed by serial pharmacokinetic sampling for 72 hours. DTG unbound concentrations at 3 and 24 hours after dosing were determined by equilibrium dialysis. Non-compartmental pharmacokinetic analysis was performed; geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated by the mixed effect model with gender, age, and body mass index as co-variates for treatment comparison.

Results:  DTG pharmacokinetics parameters using total plasma DTG concentration were similar between subjects with moderate hepatic impairment and matched healthy subjects. The geometric mean ratio (90% confidence interval) for AUC (0-∞), C_max, C24, CL/F, and t1/2 were 1.05 (0.74 to 1.49), 1.02 (0.75 to 1.37), 1.04 (0.73 to 1.48), 0.95 (0.67 to 1.34), and 1.04 (0.84 to 1.27), respectively. The percentage of unbound DTG was slightly higher in moderate hepatic impairment subjects (range 0.21% to 0.8%) compared with healthy subjects (range 0.18% to 0.3%); this correlated with lower serum albumin concentrations. Such small differences in unbound DTG concentrations are not considered clinically significant. DTG was generally well tolerated in both hepatically impaired and healthy subjects, without serious adverse events or withdrawals due to adverse events. All adverse events were reported as mild (grade 1) in severity; headache was the only adverse event reported in >1 subject, which was in the healthy group.

Conclusions:  Plasma exposures of DTG in moderate hepatically impaired subjects were similar to those in healthy subjects. No dose adjustment of DTG is required for subjects with mild to moderate hepatic impairment.