Quantitative projection of human brain penetration of the H₃ antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy

Abstract

1. Unbound brain drug concentration (C_b,u), a valid surrogate of interstitial fluid drug concentration (C_ISF), cannot be directly determined in humans, which limits accurately defining the human C_b,u:C_p,u of 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 C_b,u:C_p,u in humans and nonhuman primate (NHP).

3. In rat, PF-03654746 achieved net blood–brain barrier (BBB) equilibrium (C_b,u:C_p,u of 2.11).

4. In NHP and humans, the PET receptor occupancy-based C_p,u IC₅₀ 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 H₃ K_i (2.3 nM).

5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived C_b,u:C_p,u of PF-03654746 was integrated with C_p,u IC₅₀ to identify unbound (neuro) potency of PF-03654746, nIC₅₀.

6. The nIC₅₀ 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 H₃ K_i (2.3 nM).

7. This correlation of the nIC₅₀ and in vitro hH₃ K_i suggested the translation of net BBB equilibrium of PF-03654746 from rat to NHP and humans, and confirmed the use of C_p,u as a reliable surrogate of C_b,u.

8. Thus, nIC₅₀ quantitatively informed the human C_b,u:C_p,u of PF-03654746.

• Brain penetration
• PET
• PF-03654746
• projection
• receptor occupancy

Acknowledgements

The authors would like to acknowledge the contributions of Dr Jennifer L. Liras and Ms. Stacey Becker in PDM NCE, Pfizer.

Declaration of interest

The authors have no declarations of interest to report.

Supplementary material available online