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

Stephen Weller, Julie Borland, Shuguang Chen, Mark Johnson, Paul Savina, Brian Wynne, Toshihiro Wajima, Amanda F Peppercorn, Stephen C Piscitelli, Stephen Weller, Julie Borland, Shuguang Chen, Mark Johnson, Paul Savina, Brian Wynne, Toshihiro Wajima, Amanda F Peppercorn, Stephen C Piscitelli

Abstract

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 pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment 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 impairment (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 significant overlap between groups. DTG mean 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 impairment 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.

Trial registration: ClinicalTrials.gov NCT01353716.

Figures

Fig. 1
Fig. 1
Mean plasma DTG and DTG-Gluc concentration-time plots in subjects with and without renal impairment

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Source: PubMed

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