Abstract
PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies.
Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min−1 kg−1 for PF-184298, and 5 to >20 mL min−1 kg−1 for PF-4776548.
A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction.
A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298.
A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.
Acknowledgments
The authors gratefully acknowledge the many Pfizer colleagues, past and present, who contributed to the data described within this manuscript; Richard Mitchell, Heather Hughes, Andy Beal, Nigel Hardy, Helen Stafford, Nicola Lindsay, Jenny Gedge, Russell Jones, Katherine Fenner, Florian Wakenhut, Christopher Kohl, Charlotte Lane, Silvia Guionaud, Jessica Boyle, Mark McAllister, Suet M Wong. In addition, the authors would like to acknowledge scientists from Xceleron Limited, Jeanette Crowder and Ian Hallett, who were involved in the AMS portion of the study conducted with PF-4776548.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.