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Quantitative projection of human brain penetration of the H 3 antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy.
- Source :
-
Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2017 Feb; Vol. 47 (2), pp. 119-126. Date of Electronic Publication: 2016 Jun 29. - Publication Year :
- 2017
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Abstract
- 1. Unbound brain drug concentration (C <subscript>b,u</subscript> ), a valid surrogate of interstitial fluid drug concentration (C <subscript>ISF</subscript> ), cannot be directly determined in humans, which limits accurately defining the human C <subscript>b,u</subscript> :C <subscript>p,u</subscript> of investigational molecules. 2. For the H <subscript>3</subscript> R antagonist (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), we interrogated C <subscript>b,u</subscript> :C <subscript>p,u</subscript> in humans and nonhuman primate (NHP). 3. In rat, PF-03654746 achieved net blood-brain barrier (BBB) equilibrium (C <subscript>b,u</subscript> :C <subscript>p,u</subscript> of 2.11). 4. In NHP and humans, the PET receptor occupancy-based C <subscript>p,u</subscript> IC <subscript>50</subscript> of 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 H <subscript>3</subscript> K <subscript>i</subscript> (2.3 nM). 5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived C <subscript>b,u</subscript> :C <subscript>p,u</subscript> of PF-03654746 was integrated with C <subscript>p,u</subscript> IC <subscript>50</subscript> to identify unbound (neuro) potency of PF-03654746, nIC <subscript>50</subscript> . 6. The nIC <subscript>50</subscript> of 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 H <subscript>3</subscript> K <subscript>i</subscript> (2.3 nM). 7. This correlation of the nIC <subscript>50</subscript> and in vitro hH <subscript>3</subscript> K <subscript>i</subscript> suggested the translation of net BBB equilibrium of PF-03654746 from rat to NHP and humans, and confirmed the use of C <subscript>p,u</subscript> as a reliable surrogate of C <subscript>b,u</subscript> . 8. Thus, nIC <subscript>50</subscript> quantitatively informed the human C <subscript>b,u</subscript> :C <subscript>p,u</subscript> of PF-03654746.
Details
- Language :
- English
- ISSN :
- 1366-5928
- Volume :
- 47
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Xenobiotica; the fate of foreign compounds in biological systems
- Publication Type :
- Academic Journal
- Accession number :
- 27353353
- Full Text :
- https://doi.org/10.3109/00498254.2016.1166531