CLINICALTRIAL Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment

Purpose Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmaco-kinetics (PK), even for drugs primarily metabolized or secret-ed in bile, this study investigated the effect of renal impair-ment on the PK of DTG. Methods This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal im-pairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr>90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance. Results DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed signif-icant overlap between groups. DTGmean exposure was lower in subjects with severe renal impairment compared to healthy, matched subjects: AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impair-ment did not affect DTG fraction unbound in plasma. Conclusions The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment