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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037234.
-
ABBREVIATIONS:
- PR
- progesterone receptor
- PF-02413873
- 4-[3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile
- PK
- pharmacokinetics
- FIH
- first-in-human
- CL
- clearance
- CL/F
- oral clearance
- t1/2
- half-life
- PBPK
- physiologically based pharmacokinetic
- PBS
- phosphate-buffered saline
- PF-02339955
- 4-[3,5-dicyclopropyl-1-(methylsulfonylmethyl)-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile
- PF-02327888
- 4-[3,5-dicyclopropyl-1-(N-methyl-acetamide)-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile
- FaSSIF
- fasted state simulated intestinal fluid
- FeSSIF
- fed state simulated intestinal fluid
- HPLC
- high-performance liquid chromatography
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- Fu
- unbound fraction
- CLu
- unbound clearance
- P450
- cytochrome P450
- MRM
- multiple reaction monitoring
- CLint,app
- apparent intrinsic clearance
- PEG
- polyethylene glycol
- SSS
- single species scaling
- BW
- body weight
- CLp
- plasma clearance
- AUC
- area under the curve
- Kp
- tissue-to-plasma partition coefficient
- CLint
- intrinsic clearance
- ACAT
- Advanced Compartmental Absorption Transit
- r
- recombinant
- HLM
- human liver microsomes
- BPR
- blood/plasma ratio
- DLM
- dog liver microsomes
- RLM
- rat liver microsomes.
- Received November 12, 2010.
- Accepted April 15, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|