Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of
human immunodeficiency virus (HIV)-1 infection by GlaxoSmithKline (GSK) on behalf of
Shionogi-ViiV Healthcare LLC. DTG is metabolized primarily by uridine diphosphate
glucuronyltransferase (UGT)1A1, with a minor role of cytochrome P450 (CYP)3A, and with renal
elimination of unchanged drug being extremely low (< 1% of the dose). Fifty-three percent of
the total oral dose is excreted unchanged in the feces but it is unknown if all or part of
this is due to unabsorbed drug or some percentage of biliary excretion of the glucuronide
conjugate which can be further degraded to form the parent compound in the gut lumen. The
current Food and Drug Administration (FDA) draft guidance for renal impairment studies states
that a pharmacokinetic (PK) study in patients with renal impairment should be conducted even
for those drugs primarily metabolized or secreted in bile, because renal impairment can
inhibit some pathways of hepatic and gut drug metabolism and transport.
This study is planned as an open label, single-dose, pharmacokinetic study to evaluate plasma
DTG pharmacokinetics following oral administration to subjects with severe renal impairment
(creatinine clearance < 30 ml/min) and matched healthy controls. Results from this study are
expected to enable the development of appropriate dosing recommendations in patients with
renal impairment.