title: Quantitative projection of human brain penetration of the H3antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy.
abstract: 1. Unbound brain drug concentration (Cb,u), a valid surrogate of interstitial fluid drug concentration (CISF), cannot be directly determined in humans, which limits accurately defining the human Cb,u:Cp,uof investigational molecules. 2. For the H3R antagonist (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), we interrogated Cb,u:Cp,uin humans and nonhuman primate (NHP). 3. In rat, PF-03654746 achieved net blood-brain barrier (BBB) equilibrium (Cb,u:Cp,uof 2.11). 4. In NHP and humans, the PET receptor occupancy-based Cp,uIC50of PF-03654746 was 0.99 nM and 0.31 nM, respectively, which were 2.1- and 7.4-fold lower than its in vitro human H3Ki(2.3 nM). 5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived Cb,u:Cp,uof PF-03654746 was integrated with Cp,uIC50to identify unbound (neuro) potency of PF-03654746, nIC50. 6. The nIC50of PF-03654746 was 2.1 nM in NHP and 0.66 nM in human which better correlated (1.1- and 3.49-fold lower) with in vitro human H3Ki(2.3 nM). 7. This correlation of the nIC50and in vitro hH3Kisuggested the translation of net BBB equilibrium of PF-03654746 from rat to NHP and humans, and confirmed the use of Cp,uas a reliable surrogate of Cb,u. 8. Thus, nIC50quantitatively informed the human Cb,u:Cp,uof PF-03654746.
authors.affiliation: a Departments of Pharmacokinetics , Dynamics, and Metabolism, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Aarti
authors.initials: A
authors.lastname: Sawant-Basak
authors.affiliation: b Clinical & Translational Imaging, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Laigao
authors.initials: L
authors.lastname: Chen
authors.affiliation: c Neuroscience and Pain Research Unit, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Shaffer
authors.affiliation: d Worldwide Research and Development, Pfizer Inc. , Cambridge , MA , USA , and.
authors.forename: Donna
authors.initials: D
authors.lastname: Palumbo
authors.affiliation: a Departments of Pharmacokinetics , Dynamics, and Metabolism, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: a Departments of Pharmacokinetics , Dynamics, and Metabolism, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tseng
authors.affiliation: a Departments of Pharmacokinetics , Dynamics, and Metabolism, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Spracklin
authors.affiliation: e Department of Diagnostic Radiology , Yale University , New Haven , CT , USA.
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: e Department of Diagnostic Radiology , Yale University , New Haven , CT , USA.
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.affiliation: e Department of Diagnostic Radiology , Yale University , New Haven , CT , USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: e Department of Diagnostic Radiology , Yale University , New Haven , CT , USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: e Department of Diagnostic Radiology , Yale University , New Haven , CT , USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: b Clinical & Translational Imaging, Pfizer Inc. , Cambridge , MA , USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: McCarthy
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain; D003503:Cyclobutanes / Q000493:pharmacokinetics*; D054828:Histamine H3 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D003503:Cyclobutanes; D054828:Histamine H3 Antagonists; C569672:N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidinylmethyl)phenyl)cyclobutanecarboxamide; D011759:Pyrrolidines
keywords: Brain penetration; PET; PF-03654746; projection; receptor occupancy