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

<p>1. Unbound brain drug concentration (<i>C</i>_b,u), a valid surrogate of interstitial fluid drug concentration (<i>C</i>_ISF), cannot be directly determined in humans, which limits accurately defining the human <i>C</i>_b,u:<i>C</i>_p,u of investigational molecules.</p> <p>2. For the H₃R antagonist (1<i>R</i>,3<i>R</i>)-<i>N</i>-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (<b>PF-03654746</b>), we interrogated <i>C</i>_b,u:<i>C</i>_p,u in humans and nonhuman primate (NHP).</p> <p>3. In rat, <b>PF-03654746</b> achieved net blood–brain barrier (BBB) equilibrium (<i>C</i>_b,u:<i>C</i>_p,u of 2.11).</p> <p>4. In NHP and humans, the PET receptor occupancy-based <i>C</i>_p,u IC₅₀ of <b>PF-03654746</b> was 0.99 nM and 0.31 nM, respectively, which were 2.1- and 7.4-fold lower than its <i>in vitro</i> human H₃ <i>K</i>_i (2.3 nM).</p> <p>5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived <i>C</i>_b,u:<i>C</i>_p,u of <b>PF-03654746</b> was integrated with <i>C</i>_p,u IC₅₀ to identify unbound (neuro) potency of <b>PF-03654746</b>, <i>n</i>IC₅₀.</p> <p>6. The <i>n</i>IC₅₀ of <b>PF-03654746</b> was 2.1 nM in NHP and 0.66 nM in human which better correlated (1.1- and 3.49-fold lower) with <i>in vitro</i> human H₃ <i>K</i>_i (2.3 nM).</p> <p>7. This correlation of the <i>n</i>IC₅₀ and <i>in vitro h</i>H₃ <i>K</i>_i suggested the translation of net BBB equilibrium of <b>PF-03654746</b> from rat to NHP and humans, and confirmed the use of <i>C</i>_p,u as a reliable surrogate of <i>C</i>_b,u.</p> <p>8. Thus, <i>n</i>IC₅₀ quantitatively informed the human <i>C</i>_b,u:<i>C</i>_p,u of <b>PF-03654746</b>.</p