title: 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.affiliation: Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, CT 06340, USA. amit.kalgutkar@pfizer.com
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Meera
authors.initials: M
authors.lastname: Tugnait
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Miao
authors.forename: Vincent
authors.initials: V
authors.lastname: Mascitti
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.forename: Beijing
authors.initials: B
authors.lastname: Tan
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walsky
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chupka
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Robinson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics* / Q000494:pharmacology; D018938:Caco-2 Cells; D018592:Cross-Over Studies; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008875:Middle Aged; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D051247:Sodium-Glucose Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D051247:Sodium-Glucose Transport Proteins; C570288:ertugliflozin; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase