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

Eur J Clin Pharmacol. 2014 Jan;70(1):29-35. doi: 10.1007/s00228-013-1590-9. Epub 2013 Oct 6.

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.

Publication types

  • Clinical Trial, Phase I
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • HIV Integrase Inhibitors / adverse effects
  • HIV Integrase Inhibitors / blood
  • HIV Integrase Inhibitors / pharmacokinetics*
  • Heterocyclic Compounds, 3-Ring / adverse effects
  • Heterocyclic Compounds, 3-Ring / blood
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Humans
  • Male
  • Middle Aged
  • Renal Insufficiency / metabolism*

Substances

  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • dolutegravir

Associated data

  • ClinicalTrials.gov/NCT01353716