A Phase 1 Oral Mass Balance and Combined Intravenous [14C] Microtracer Study to Characterize the Absorption, Metabolism, Excretion, and Pharmacokinetics of Antitumor Drug E7386 in Humans.

E7386, an orally active protein-protein interaction inhibitor, is reported to impair the interaction between transcriptional co-activator CREB-binding protein and β-catenin. A competent study design exploring the concomitant dosing routes, sensitive intravenous (IV; [14C]) microtracer technology, and oral [14C] radiolabeled dosing was successfully implemented to determine the absolute bioavailability and the absorption, metabolism, and excretion (AME) properties of E7386 in healthy adult participants. In Part 1, 7 participants received a single 40 mg immediate release (IR) tablet of E7386 followed by an IV infusion containing a microtracer solution of 14C-labeled E7386 ([14C]E7386; 100 µg). In Part 2, 8 participants received a single 40 mg powder-in-capsule oral administration of radiolabeled [14C]E7386 (80 µCi). The radiolabeled IV [14C] microtracer arm assessed the absorption, absolute oral bioavailability (F), and first-pass effect of E7386. The geometric mean (CV%) absolute bioavailability of E7386 was found to be 23.6% (34.6), which may be attributed to the insufficient absorption, extensive first-pass and rapid systemic metabolism of E7386. The mean (SD) cumulative recovery of 14C total radioactivity was 87.9% (6.56) after collection of excreta for up to a maximum of 480 hours postdose. Of the total administered dose, 85.1% was recovered in feces, 0.371% in toilet tissue, and 2.36% in urine. These results suggest that [14C]E7386-related material is predominantly excreted in feces after oral administration. Overall, IV administration and oral administration of a single E7386 dose was tolerable in healthy participants, and adverse events were manageable.