Authors :
Presenting Author: Nuggehally Srinivas, PhD, FCP – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Jonathan Williams, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Rajareddy Kallem, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Shikha Polega, PharmD – H. Lundbeck A/S, Copenhagen, Denmark
Anne Kümmel, PhD – IntiQuan GmbH, Basel, Switzerland
Darius Schweinoch, PhD – IntiQuan GmbH, Basel, Switzerland
Rosa Chan, PhD – Longboard Pharmaceuticals (now a part of H. Lundbeck A/S)
Rationale:
Bexicaserin is an oral, highly selective 5-hydroxytryptamine 2C (5-HT2C) receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies (DEEs). Given routine polypharmacy in this population, bexicaserin will frequently be used with other antiseizure medications (ASMs). Therefore, it is important to evaluate and characterize the drug–drug interaction (DDI) potential of bexicaserin. The objective of this analysis was to evaluate whether co-administered ASMs identified as precipitants (perpetrators) of DDIs associated with CYP/UGT enzymes may change the pharmacokinetics (PK) of bexicaserin.
Methods:
Concomitantly administered ASMs with bexicaserin in the randomized, double-blind, Phase 1b/2a PACIFIC trial (RCT) were classified as CYP inhibitors, CYP inducers, UGT inhibitors, UGT inducers, UGT substrates, or others. A population PK (PopPK) model for bexicaserin and M20, the major glucuronide metabolite of bexicaserin, was established on the RCT and pooled Phase 1 clinical trials. The RCT enrolled participants with DEEs taking stable doses of 1-4 co-administered ASMs. Effects of co-administration of these ASMs were explored as part of the covariate analysis during model development, considering a categorical covariate for each ASM category (ie, co-administration: “with” [yes]/“without” [no]). Individual bexicaserin and M20 average concentrations at steady state (Cavg) for participants in the RCT were derived for the 12-mg TID dosing frequency for individual post hoc parameter estimates and compared between the various assigned ASM categories in boxplot figures based on their respective precipitant mechanisms.
Results:
20 ASMs were included in the analysis, with 13 inhibitors or inducers of CYP/UGT enzymes and 7 DDI precipitants by other mechanisms, thus providing a broad evaluation of the precipitant effect of ASMs on the PK of bexicaserin. The simulated individual bexicaserin and M20 Cavg at steady state for 12-mg TID dosing showed a similar spread of bexicaserin exposures for “with” (yes) and “without” (no) ASM co-medications. The central distribution of “with/without” across the different ASM categories was also generally similar.
Conclusions:
In conclusion, the simulated bexicaserin and M20 Cavg values at steady state upon 12-mg TID dosing were similar in participants “with” and “without” all categories of co-administered enzyme inhibiting/inducing ASMs. Our results indicate low risk of CYP-mediated clinical DDI potential for bexicaserin when co-administered with the ASMs evaluated. These data enabled a broad evaluation of the DDI potential of bexicaserin as an object (victim) and demonstrated no apparent clinically meaningful effect on the PK of bexicaserin or M20. Moreover, the data suggests that bexicaserin dosage adjustments are unlikely needed when co-administered with the commonly prescribed ASMs evaluated in this study.
Funding:
This study was sponsored by Longboard Pharmaceuticals (now a part of H. Lundbeck A/S; La Jolla, CA, USA).