Abstracts

Rationale: Bexicaserin is an oral, centrally acting, highly selective 5-HT_2C superagonist in development for treatment of patients with developmental and epileptic encephalopathies (DEEs). Given routine polypharmacy in this population, it is anticipated bexicaserin will frequently be used with other ASMs. Therefore, avoidance of drug-drug-interactions (DDIs) is desirable, and it is important to thoughtfully evaluate and characterize bexicaserin’s DDI potential. Bexicaserin undergoes primary metabolism via UDP-glucuronosyltransferase (UGT) and has previously reported a low victim potential for a variety of CYP enzymes. The objective of this study was to evaluate the influence of bexicaserin on substrates of various renal, hepatic, and efflux transporters, as well as CYP/UGT enzymes using a cocktail approach, where more than one index probe substrate is administered simultaneously to assess several drug metabolizing enzymes or transporters in a single study. Here, the effect of bexicaserin as a potential perpetrator of DDIs is evaluated.

Methods: This was a non-randomized, fixed-sequence, open-label clinical study in 15 healthy, human volunteers. Assessments were performed without and with co-administration of bexicaserin. Multiple doses of bexicaserin 12 mg three times daily (TID) were investigated using two distinct probe substrate drug cocktails. Cocktail 1 was comprised of lorazepam (UGT pathway) and rosuvastatin (BCRP, OATP1B1 and OATP1B3); Cocktail 2 was comprised of caffeine (CYP1A2), metformin (OCT1 and OCT2, MATE-2K, and MATE1), and furosemide (OAT1 and OAT3). Serial plasma samples were collected on pre-specified pharmacokinetic (PK) days for bexicaserin and the respective probe substrate drug cocktails. Plasma samples were analyzed for the appropriate probe substrate and metabolite(s).

Results: In Cocktails 1 and 2, plasma exposures to the five probe substrates and/or their respective metabolite(s) were generally comparable in the presence or absence of bexicaserin. Cocktail 1: PK data were indicative of a lack of drug interaction by bexicaserin on the disposition of the probe substrates via UGT pathway, BCRP, OATP1B1, OATP1B3. Cocktail 2: PK data were indicative of a lack of drug interaction by bexicaserin on the disposition of probe substrates via OCT1, OCT2, MATE-2K, and MATE1. For CYP1A2, the AUC_last of caffeine increased by ~61%, with an increase of ~18% of its metabolite paraxanthine, suggestive of bexicaserin acting as a weak inhibitor of CYP1A2. For OAT1 and OAT3, data of furosemide was suggestive of a weak interaction.


Conclusions: These data support the low likelihood of bexicaserin acting as a perpetrator for clinically relevant DDIs via CYP1A2, UGT, liver transporters (BCRP, OATP1B1 and OATP1B3), and/or renal transporters (OCT1, OCT2, MATE-2K, MATE1, OAT1, and OAT3). Dosage adjustments of co-administered drugs that are metabolized via the metabolic/transporter pathways evaluated in this study appears unlikely.

Funding: This study was sponsored by Longboard Pharmaceuticals, Inc.