title: Preclinical and clinical pharmacokinetics of PF-02413873, a nonsteroidal progesterone receptor antagonist.
abstract: The recently discovered selective nonsteroidal progesterone receptor (PR) antagonist 4-[3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile (PF-02413873) was characterized in metabolism studies in vitro, in preclinical pharmacokinetics in rat and dog, and in an initial pharmacokinetic study in human volunteers. Clearance (CL) of PF-02413873 was found to be high in rat (84 ml · min(-1) · kg(-1)) and low in dog (3.8 ml · min(-1) · kg(-1)), consistent with metabolic stability determined in liver microsomes and hepatocytes in these species. In human, CL was low in relation to hepatic blood flow, consistent with metabolic stability in human in vitro systems, where identified metabolites suggested predominant cytochrome P450 (P450)-catalyzed oxidative metabolism. Prediction of CL using intrinsic CL determined in human liver microsomes (HLM), recombinant human P450 enzymes, and single species scaling (SSS) from pharmacokinetic studies showed that dog SSS and HLM scaling provided the closest estimates of CL of PF-02413873 in human. These CL estimates were combined with a physiologically based pharmacokinetic (PBPK) model to predict pharmacokinetic profiles after oral suspension administration of PF-02413873 in fasted and fed states in human. Predicted plasma concentration versus time profiles were found to be similar to those observed in human over the PF-02413873 dose range 50 to 500 mg and captured the enhanced exposure in fed subjects. This case study of a novel nonsteroidal PR antagonist underlines the utility of PBPK modeling techniques in guiding prediction confidence and design of early clinical trials of novel chemical agents.
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Pfizer Worldwide Research & Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. peter.bungay@pfizer.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bungay
authors.forename: Sarah
authors.initials: S
authors.lastname: Tweedy
authors.forename: David C
authors.initials: DC
authors.lastname: Howe
authors.forename: Karl R
authors.initials: KR
authors.lastname: Gibson
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Mount
mesh_terms: D000818:Animals; D001711:Biotransformation; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007419:Intestinal Secretions / Q000737:chemistry; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011485:Protein Binding; D011720:Pyrazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D012995:Solubility; D013045:Species Specificity; D013450:Sulfones / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: C568445:4-(3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl)oxy-2,6-dimethylbenzonitrile; D011720:Pyrazoles; D011980:Receptors, Progesterone; D013450:Sulfones