(M0930-10-57) Open Label, Single Center, 2 Part Parallel Study to Determine the Absolute Bioavailability and the Absorption, Metabolism, and Elimination Properties of [¹⁴C]E7386 in Healthy Male Subjects

Purpose: E7386 has been shown to inhibit the interaction between CBP and β-catenin, leading to Wnt pathway modulation. This 2-part, parallel study was designed to determine the absolute bioavailability and the absorption, metabolism, and elimination properties of [¹⁴C]E7386 in healthy male subjects. The primary objectives of the study included: the determination of absolute bioavailability of E7386 (Part 1); and to determine the pharmacokinetics (PK) and excretion of E7386 following a single 40 mg oral administration of [¹⁴C]E7386 (Part 2). The study also aimed to assess the safety and tolerability of E7386 in healthy male subjects.

Methods: In Part 1, subjects received a single oral 40 mg dose of E7386 followed by an IV infusion containing a microdose solution of [¹⁴C]E7386 (100 µg). In Part 2, subjects received a single 40 mg powder in capsule oral administration of radiolabeled [¹⁴C]E7386 (80 μCi). A total of 15 healthy adult male subjects (7 subjects in Part 1 and 8 subjects in Part 2) completed the study.

Results: The geometric mean (%CV) absolute bioavailability of oral E7386 (n=6) was determined to be 23.6% (34.6). One of the subjects in Part 1 was excluded from IV PK analysis due to infusion pump error. The mean (SD) cumulative recovery of total radioactivity (TRA) was 87.9% (6.56) after collection of excreta for up to a maximum of 480 hours postdose (n=8). Of the dose administered, 85.1% was recovered in feces, and 2.36% was recovered in urine. Toilet tissues were also analyzed over the study duration for each subject, with a mean (SD) of 0.371% (0.814) of the administered radioactivity recovered. Concentrations of TRA were lower in whole blood compared to plasma, indicating very limited partitioning of the drug into blood cells. There were no clinically significant adverse events (AEs) reported during the treatment duration. Most of the reported AEs were predominantly mild or moderate in severity and resolved spontaneously or with standard care.

Conclusion: The geometric mean (% CV) absolute bioavailability of E7386 was found to be 23.6% (34.6). This may be attributed to rapid first-pass and systemic metabolism of E7386. The use of radiolabelled microdose IV arm was invaluable in the assessment of absorption, absolute oral bioavailability, and the first-pass effects of E7386. Results suggest that [¹⁴C]E7386-related material is predominantly excreted in feces after oral administration. The proportion recovered in feces after oral administration may include unabsorbed E7386. Overall, intravenous administration and oral administration of a single 40 mg E7386 dose was tolerable in healthy male subjects and the adverse events were manageable.