Preclinical species and human disposition of PF-04971729, a selective inhibitor of the sodium-dependent glucose cotransporter 2 and clinical candidate for the treatment of type 2 diabetes mellitus.

Abstract

(1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (PF-04971729), a potent and selective inhibitor of the sodium-dependent glucose cotransporter 2, is currently in phase 2 trials for the treatment of diabetes mellitus. This article describes the preclinical species and in vitro human disposition characteristics of PF-04971729 that were used in experiments performed to support the first-in-human study. Plasma clearance was low in rats (4.04 ml · min(-1) · kg(-1)) and dogs (1.64 ml · min(-1) · kg(-1)), resulting in half-lives of 4.10 and 7.63 h, respectively. Moderate to good bioavailability in rats (69%) and dogs (94%) was observed after oral dosing. The in vitro biotransformation profile of PF-04971729 in liver microsomes and cryopreserved hepatocytes from rat, dog, and human was qualitatively similar; prominent metabolic pathways included monohydroxylation, O-deethylation, and glucuronidation. No human-specific metabolites of PF-04971729 were detected in in vitro studies. Reaction phenotyping studies using recombinant enzymes indicated a role of CYP3A4/3A5, CYP2D6, and UGT1A9/2B7 in the metabolism of PF-04971729. No competitive or time-dependent inhibition of the major human cytochrome P450 enzymes was discerned with PF-04971729. Inhibitory effects against the organic cation transporter 2-mediated uptake of [(14)C]metformin by PF-04971729 also were very weak (IC(50) = ∼900 μM). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies after oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response.

• Authors: Amit S Kalgutkar, Meera Tugnait, Tong Zhu, Emi Kimoto, Zhuang Miao, Vincent Mascitti, Xin Yang, Beijing Tan, Robert L Walsky, Jonathan Chupka, Bo Feng, Ralph P Robinson
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 39 Issue 9 Pg. 1609-19 (Sep 2011) ISSN: 1521-009X [Electronic] United States
• PMID: 21690265 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Cytochrome P-450 Enzyme Inhibitors
• Sodium-Glucose Transport Proteins
• ertugliflozin
• Cytochrome P-450 Enzyme System
• Glucuronosyltransferase

Topics

• Administration, Oral
• Adult
• Animals
• Biological Availability
• Biotransformation
• Bridged Bicyclo Compounds, Heterocyclic (pharmacokinetics, pharmacology)
• Caco-2 Cells
• Cross-Over Studies
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (metabolism)
• Dogs
• Drug Evaluation, Preclinical
• Female
• Glucuronosyltransferase (metabolism)
• HEK293 Cells
• Hepatocytes (drug effects, enzymology, metabolism)
• Humans
• Intestinal Absorption
• Male
• Microsomes, Liver (enzymology, metabolism)
• Middle Aged
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Sodium-Glucose Transport Proteins (antagonists & inhibitors, metabolism)
• Young Adult