POS-393 PHARMACOKINETICS OF DAPRODUSTAT AND METABOLITES IN SUBJECTS WITH NORMAL AND IMPAIRED HEPATIC FUNCTION

Abstract

Daprodustat is a prolyl hydroxylase inhibitor in development for treatment of anemia of chronic kidney disease. This study assessed the effect of mild and moderate hepatic impairment (HI) on daprodustat pharmacokinetics (PK) and pharmacodynamics (PD). In this open-label, non‑randomized, parallel‑study in healthy subjects (HS) and mild and moderate HI subjects (defined by Child-Pugh), a single 6 mg dose of daprodustat was administered to 37 subjects: 9 HS matched to 12 mild HI and 8 HS matched to 8 moderate HI. PK was analyzed for daprodustat and 6 metabolites. Peak exposure (Cmax) of daprodustat was comparable in mild HI and HS; however, overall exposure (AUC) was increased 1.5-fold in mild HI compared with HS. For all metabolites, Cmax AUC in mild HI were increased 1.3- to 2.0-fold compared with HS. In moderate HI, daprodustat Cmax and AUC were increased 2.0-fold compared with HS. Metabolite results aligned with parent drug PK, with a 1.2- to 1.7-fold increase in Cmax and AUC, in moderate HI compared with HS. The only exception was GSK2531401 (M13) Cmax which was similar. Unbound daprodustat concentrations reflect total daprodustat exposure, with a 2.2- and 2.3-fold increase in exposure (free AUC) observed in mild and moderate HI, respectively, compared with HS. Erythropoietin concentrations at baseline and following daprodustat administration were generally higher in mild and moderate HI vs HS. There were no deaths, serious adverse events, or apparent difference in safety between the groups. As daprodustat is titrated to hemoglobin target, the observed increases in exposure in subjects with mild or moderate HI, when compared with HS from this study and historical PK, are not expected to be of clinical significance or pose any safety concerns.