Pharmacokinetics and metabolism of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator, in rats and monkeys.

ABSTRACT

The metabolic profiles and pharmacokinetics of pemafibrate, a novel selective peroxisome proliferator activated receptor-alpha modulator currently launched as an antidyslipidemic drug, were investigated in vitro using hepatocytes from rats, monkeys and humans and in vivo in rats and monkeys. Hepatocytes from rats, monkeys and humans all biotransformed pemafibrate to its demethylated form (M1). The bioavailabilities of pemafibrate in Sprague-Dawley rats and cynomolgus monkeys were 15% and 87%, respectively, after a single oral administration of pemafibrate (1 mg/kg). In rat plasma, unmetabolized pemafibrate was the major form, accounting for 29% of the area under the curve (AUC) of total radioactivity. In monkey plasma, in contrast, the major circulating metabolites were M2/3 (dearylated/dicarboxylic acid forms, 15%), M4 (N-dealkylated form, 21%) and M5 (benzylic oxidative form, 9%), but pemafibrate was the notable minor form (3%). These results, in combination with the reported findings in humans, suggest that the metabolite profile of pemafibrate in plasma was different for rats and monkeys, and that monkeys could be a suitable animal model for further pharmacokinetic studies of pemafibrate in humans.