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

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 carrier-phenotyping” 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 predicted within 20% error when considering transporter-enzyme interplay in a physiologically-based 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.

SIGNIFICANCE STATEMENT This work characterizes the transport/metabolic pathways in the hepatic disposition of PF-06835919, a first-in-class ketohexokinase (KHK) inhibitor for the treatment of metabolic disorders and NASH. Phenotyping studies using transfected systems, human hepatocytes, and liver microsomes signify the role of OAT2 and OATP1B1 in the hepatic uptake and multiple enzymes in the metabolism of PF-06835919. Data presented suggest hepatic transporter-enzyme interplay in determining its systemic concentrations and potential enrichment in liver, a target site for KHK inhibition.

FootnotesReceived May 22, 2022.Accepted June 27, 2022.

No funding was received for the work reported here.

All authors are full-time employees of Pfizer Inc. The authors have no conflicts of interest that are directly relevant to this study.

dx.doi.org/10.1124/dmd.122.000953.

Embedded ImageEmbedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics

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