Preclinical and Clinical Pharmacokinetics of PF-02413873, a Nonsteroidal Progesterone Receptor Antagonist

Abstract

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 ⅐ min ؊1 ⅐ kg ؊1) and low in dog (3.8 ml ⅐ min ؊1 ⅐ 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.

The Translational Efficacy of a Nonsteroidal Progesterone Receptor Antagonist, 4-[3-Cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873), on Endometrial Growth in Macaque and Human

“…To this latter point, one of the anticipated pharmacological consequences of PR antagonism is an upregulation of AR expression in the endometrium, especially when assessed during luteal phase sampling (Slayden et al, 2001b;Brenner et al, 2002Brenner et al, , 2003Narvekar et al, 2004;Slayden and Brenner, 2004;Heikinheimo et al, 2007; by undertaking a clinical evaluation in healthy female subjects. PF-02413873 had been previously assessed in a preliminary single-dose escalation to determine PK, safety, and toleration (Bungay et al, 2011). PF-02413873 was considered safe and well tolerated up to the maximal dose tested (3 g) and behaved with a terminal half-life of approximately 40 h (Bungay et al, 2011).…”

“…PF-02413873 had been previously assessed in a preliminary single-dose escalation to determine PK, safety, and toleration (Bungay et al, 2011). PF-02413873 was considered safe and well tolerated up to the maximal dose tested (3 g) and behaved with a terminal half-life of approximately 40 h (Bungay et al, 2011). These data were used to underwrite a 14-day, multiple-dose, double-blind, third-party open, randomized, and placebo-controlled study to determine the effects of PF-02413873 on endometrial growth and ovarian function.…”

Dose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches

“…This approach has been validated by a number of different authors using diverse drug datasets (8,10,11,71). Specific examples of successful prospective predictions of human PK using PBPK modelling can be found in the literature (72)(73)(74). These publications provide examples of where PBPK modelling has been used to design first-in-human clinical trials.…”

“…In later drug development stages, the model can be updated with animal data specific to the therapeutic mAb to enable translation from preclinical species to human populations. We will illustrate fit- Prospective prediction of first-in-human PK in healthy volunteers (72)(73)(74) Retrospective prediction of first-in-human PK in healthy volunteers (8-11, 16,71) Prediction of PK in paediatric populations (78)(79)(80)(81)(82) Prediction of PK in patients with hepatic impairment/ liver cirrhosis (75,76) Prediction of PK in patients with renal impairment (77,86,87) Predictions of PK in other patient populations (83)(84)(85) Predictions of PK in polymorphic populations (88) for-purpose PBPK models using one example from literature and one in-house example. Adalimumab is an anti-TNF-alpha mAb approved for the treatment of rheumatoid arthritis (RA), an autoimmune disease which leads to inflammation of joints.…”

Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin

“…However, it should be emphasized that these simulations are quite dependent on the quality of the input parameters and mechanistic understanding of the processes driving PK. A number of more detailed case studies using in silico program are also available in the literature illustrating the value of such modeling and simulation techniques [1415161718]. …”