Investigation of pharmacokinetic drug interaction between clesacostat and DGAT2 inhibitor ervogastat in healthy adult participants

Abstract Co‐administration of clesacostat (acetyl‐CoA carboxylase inhibitor, PF‐05221304) and ervogastat (diacylglycerol O‐acyltransferase inhibitor, PF‐06865571) in laboratory models improved non‐alcoholic fatty liver disease (NAFLD)/non‐alcoholic steatohepatitis (NASH) end points and mitigated clesacostat‐induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion‐transporting polypeptide‐mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); in vitro clesacostat is identified as a potential CYP3A time‐dependent inactivator. In vitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer‐term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non‐randomized, open‐label, fixed‐sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1–7) and co‐administered with ervogastat 300 mg b.i.d. (Days 8–14). Mean systemic clesacostat exposures, when co‐administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration–time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1–7) and co‐administered with clesacostat 15 mg b.i.d. (Days 8–14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co‐administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co‐administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD

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