PII-073 - MASS BALANCE, METABOLISM, AND EXCRETION OF [14C] BEXICASERIN IN A SINGLE DOSE RADIOLABEL STUDY IN HEALTHY ADULT MALES.

J. Williams¹, R. Chan², N. Srinivas³, R. Kallem¹, M. Le¹, C. Orevillo³, R. Kaye⁴; ¹Longboard Pharmaceuticals, San Diego, CA, United States, ²Longboard Pharmaceuticals, La Jolla, CA, USA, ³Longboard Pharmaceuticals, LA JOLLA, United States, ⁴Longboard Pharmaceuticals, LA JOLLA, CA, United States.

Background: Bexicaserin (LP352) is a potent and selective 5-hydroxytryptamine 2C superagonist undergoing clinical evaluation for the treatment of seizures associated with developmental and epileptic encephalopathies. Bexicaserin undergoes metabolism to form pharmacologically inactive metabolites. The objective of this clinical study was to evaluate the mass balance of the excretory pathways and characterize the pharmacokinetics of bexicaserin and its metabolites in the plasma.

Methods: This was a Phase 1, open-label, mass balance study to characterize the absorption, metabolism, and excretion of [14C] LP352 following a single oral dose in 8 participants. Participants were healthy males, 18 to 50 years of age with a body mass index between 18 and 32 kg/m2.
Blood, urine, and fecal samples were collected for analysis of total radioactivity; plasma and urine were analyzed for concentrations of bexicaserin, M9, M12, and M20.
Noncompartmental pharmacokinetic analysis was conducted to calculate plasma and urinary pharmacokinetic parameters of bexicaserin/metabolites.

Results: Overall, 92.3% of administered radioactivity was recovered in excreta, with an average of 87.1% in the urine and 5.2% in the feces. Parent bexicaserin represented less than 5% of the radioactivity recovered in urine, indicating that [14C] LP352 is largely eliminated via hepatic metabolism and renal excretion.
Assessment of the overlaid concentration versus time profiles suggests that bexicaserin and these 3 inactive metabolites collectively accounted for the majority of circulating radioactivity, with a glucuronide metabolite, M20, being most abundant.

Conclusion: It was a successful mass balance study since recovery of > 90% of administered radioactivity was achieved with overwhelming contribution of urinary excretion (87.1%) compared to fecal excretion (5.2%). The low levels of parent bexicaserin in the urine ( < 5% of dose) indicate that metabolism was the primary elimination route. The radioactivity profile and total pooled data of bexicaserin and inactive metabolites confirmed the absence of significant unidentified circulatory metabolites in human plasma; further, M20 was responsible for the majority of circulatory radioactivity in plasma.