PII-100 - POPULATION PHARMACOKINETIC ANALYSIS OF THE SUBLINGUAL FILM FORMULATION OF DEXMEDETOMIDINE (BXCL501) IN HEALTHY VOLUNTEERS AND ADULTS WITH SCHIZOPHRENIA OR BIPOLAR DISORDER.

H. Lagraauw¹, A. Adedoyin², C. Lathia², L. Lindbom³, F. Jonsson³; ¹qPharmetra, LLC, Njimegen, The Netherlands, ²BioXcel Therapeutics, New Haven, CT, USA, ³qPharmetra, LLC, Stockholm, Sweden.

Background: BXCL501, an orally dissolving film of dexmedetomidine, was developed as a treatment for acute agitation associated with schizophrenia and bipolar disorder in adults. It is designed to be self-administered either sublingually or buccally. A population pharmacokinetic (PK) model of sublingual dexmedetomidine is presented that integrates all available PK data.

Methods: PK data were pooled from three Phase 1 and two Phase 3 studies, in which sublingual and/or intravenous (IV) dexmedetomidine were given to healthy volunteers (HV) and adults with schizophrenia or bipolar disorder. In total, 5,388 PK observations from 642 subjects were included. The analysis was carried out using NONMEM version 7.4. The final model was validated using goodness of fit plots and prediction corrected visual predictive checks.

Results: The final 2-compartment PK model disposition parameters were estimated as follows: clearance: 34.6 L/h, central volume of distribution (V): 99.2 L, intercompartmental clearance between V and peripheral volume (V2): 58.2 L/h, and peripheral volume of distribution (V2): 32.9 L. Absolute bioavailability in healthy volunteers was estimated to be 71.2%. The transit compartment absorption model (TCAM) parameters of mean transit time (MTT) and number of transition compartments (NTR) were estimated to be 1.16 h, and 0.937, respectively. Buccal versus sublingual administration affected bioavailability and NTR. In addition, film orientation affected NTR, and a patient vs healthy volunteer effect on bioavailability was found.

Conclusion: BXCL501 PK was well-characterized by a two-compartment PK model with linear elimination and a TCAM. Absorption process could be impacted by different factors.