Effect of Food and Gemfibrozil on the Pharmacokinetics of the Novel Prolyl Hydroxylase Inhibitor GSK1278863

Anemia, a frequent complication of chronic kidney disease, is most commonly treated with recombinant human erythropoiesis-stimulating agents. Oral administration of GSK1278863, a prolyl hydroxylase inhibitor, results in the accumulation of hypoxia-inducible factor 1 alpha, and stimulates erythropoiesis by triggering the pathways involved in innate hypoxia. In vitro biotransformation data indicate that GSK1278863 is primarily metabolized by CYP2C8. This study assessed the pharmacokinetics of single-dose (100 mg) GSK1278863 administered alone, or co-administered with a high-fat/high-calorie meal or steady-state gemfibrozil (a strong CYP2C8 and OATP1B1 inhibitor). Co-administration of single-dose 100 mg GSK1278863 with a high-fat/high-calorie meal did not significantly affect the plasma exposure of GSK1278863 or its 6 predominant metabolites. Co-administration of GSK1278863 with steady-state gemfibrozil resulted in an 18.6-fold increase in the area under the curve from time 0 to infinity (AUC((0-infinity))) of GSK1278863. Additionally, the maximum plasma concentration (C-max) and terminal elimination half-life increased 3.92- and 3.70-fold, respectively. The appearance of metabolites was delayed, and their C-max and AUC((0-infinity)) were reduced by at least 90% and 62%, respectively. These findings indicate that GSK1278863 can be safely administered without regard to food. Until further studies with weaker CYP2C8 inhibitors are conducted, co-administration of GSK1278863 with CYP2C8 inhibitors should be avoided.