title: Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms.
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.
authors: Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Sandwich Laboratories, Sandwich, Kent, UK. anthony_charles.harrison@roche.com
authors: Anthony
authors: A
authors: Harrison
authors: Iain
authors: I
authors: Gardner
authors: Tanya
authors: T
authors: Hay
authors: Maurice
authors: M
authors: Dickins
authors: Kevin
authors: K
authors: Beaumont
authors: Alex
authors: A
authors: Phipps
authors: Lynn
authors: L
authors: Purkins
authors: Gill
authors: G
authors: Allan
authors: Rachelle
authors: R
authors: Christian
authors: Jonathan
authors: J
authors: Duckworth
authors: Ian
authors: I
authors: Gurrell
authors: Sarah
authors: S
authors: Kempshall
authors: Mark
authors: M
authors: Savage
authors: Mark
authors: M
authors: Seymour
authors: Marie
authors: M
authors: Simpson
authors: Louise
authors: L
authors: Taylor
authors: Paul
authors: P
authors: Turnpenny
mesh_terms: D000328:Adult; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000826:Animal Testing Alternatives; D000818:Animals; D004285:Dogs; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009287:Naphthyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010599:Pharmacokinetics; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D013223:Statistics as Topic; D055815:Young Adult
chemical_list: D000813:Anilides; D009287:Naphthyridines; D011759:Pyrrolidines; D017367:Selective Serotonin Reuptake Inhibitors; C571105:3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo(2,3-c)(1,7)naphthyridin-6-one; C544972:PF 184,298