S. W.S. Yapa,1 B. M. Johnson,1 R. Ravindranath,2 S. Caltabiano,3 A. R. Cobitz3; 1GlaxoSmithKline, Research Triangle Park, NC, 2GlaxoSmithKline, Bangalore, India, 3GlaxoSmithKline, King of Prussia, PA

BACKGROUND: GSK1278863 is in development for the treatment of anemia associated with chronic kidney disease (CKD). Given the kidney is a site of drug elimination, an understanding of the PK of GSK1278863 in subjects with renal impairment, including hemodialysis-dependent (HD), is needed.
METHODS: A Phase I repeat-dose open-label study was conducted. A 5 mg once daily dose of GSK1278863 was administered for 14 days to 8 healthy subjects and 6 subjects with Stage 3/4 CKD, and for 15 days to 8 HD subjects. PK samples were collected after single and repeat dosing (dialysis and non dialysis days for HD subjects) for analysis of GSK1278863 and 6 metabolites. Plasma protein binding, urine and dialysis clearance were also assessed.
RESULTS: PK of GSK1278863 was comparable in all groups; however Cmax was ~20% lower in renal impaired subjects. GSK1278863 had no appreciable renal or dialysis clearance. For all metabolites the steady-state AUC was 1.6- to 2.9-fold and Cmax 1.1- to 1.3-fold higher in subjects with Stage 3/4 and 5 HD (dialysis day) CKD than in subjects with normal renal function. Lower AUC (0.45-0.58 fold) and Cmax (0.58-0.71 fold) was observed on a dialysis day compared to a non dialysis day; the apparent terminal half-life were comparable. For all metabolites, 1.1-4.5% of dose was excreted in urine in normal subjects and 0.78-3.0% in subjects with renal impairment. All metabolites underwent dialysis clearance (140-167 mL/min). There were no deaths, serious adverse events, withdrawals, or apparent difference in safety between the groups.
CONCLUSION: The PK of GSK1278863 was not significantly altered in subjects with renal impairment. On the contrary, the PK of metabolites was influenced by renal function and underwent dialysis clearance.