An Exploratory, Open Label, Randomized, Parallel Group Study To Investigate The Pharmacokinetics Of Single Intravenous And Oral Micro Doses Of [14-C]-PF-04776548 In Healthy Male Subjects

To investigate the pharmacokinetics of PF-04776548 following administration of a micro-dose of PF-04776548 via both intravenous and oral routes.

Start Date01 Jan 2010

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with PF-4776548

100 Translational Medicine associated with PF-4776548

100 Patents (Medical) associated with PF-4776548

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01 Jan 2012·XenobioticaQ4 · MEDICINE

Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms

Q4 · MEDICINE

Article

Author: Mark Seymour ; Sarah Kempshall ; Marie Simpson ; Iain Gardner ; Anthony Harrison ; Ian Gurrell ; Rachelle Christian ; Lynn Purkins ; Paul Turnpenny ; Mark Savage ; Louise Taylor ; Tanya Hay ; Kevin Beaumont ; Gill Allan ; Alex Phipps ; Jonathan Duckworth ; Maurice Dickins

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.

100 Deals associated with PF-4776548

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 1	GB	Pfizer Inc.	01 Jan 2010

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