Transporter-Enzyme Interplay in the Pharmacokinetics of PF-06835919, a First-In-Class Ketohexokinase Inhibitor for Metabolic Disorders and Nonalcoholic Fatty Liver DiseaseS

Abstract

Excess dietary fructose consumption promotes metabolic dysfunction, thereby increasing the risk of obesity, type 2 diabetes, nonalcoholic steatohepatitis (NASH), and related comorbidities. PF-06835919, a first-in-class ketohexokinase inhibitor, showed reversal of such metabolic disorders in preclinical models and clinical studies and is under clinical development for the potential treatment of NASH. In this study, we evaluated the transport and metabolic pathways of PF-06835919 disposition and assessed pharmacokinetics in preclinical models. PF-06835919 showed active uptake in cultured primary human hepatocytes and substrate activity to organic anion transporter (OAT)2 and organic anion transporting polypeptide (OATP)1B1 in transfected cells. "solute carrierphenotyping"studies in human hepatocytes suggested contribution of passive uptake and OAT2- and OATP1B-mediated transport to the overall uptake to be about 15%, 60%, and 25%, respectively. PF- 06835919 showed low intrinsic metabolic clearance in vitro and was found to be metabolized via both oxidative pathways (58%) and acyl glucuronidation (42%) by CYP3A, CYP2C8, CYP2C9, and UGT2B7. After intravenous dosing, PF-06835919 showed low clearance (0.4-1.3 ml/min/kg) and volume of distribution (0.17-0.38 l/kg) in rats, dogs, and monkeys. Human oral pharmacokinetics are predictedwithin 20% error when considering transporter-enzyme interplay in a physiologicallybased pharmacokinetic model. Finally, unbound liver-to-plasma ratio (Kpuu) measured in vitro using rat, monkey, and human hepatocytes was found to be approximately 4, 25, and 10, respectively. Similarly, liver Kpuu in rat and monkey after intravenous dosing of PF-06835919 was found to be 2.5 and 15, respectively, and notably higher than the muscle and brain Kpuu, consistent with the active uptake mechanisms observed in vitro.