027: Application of Modeling & Simulation to Quantitatively Assess Ulotaront Metabolism & the Effect of a CYP450 Inhibitor in Healthy Subjects

Statement of Purpose: Ulotaront is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity and is currently in Phase 3 studies for the potential treatment of schizophrenia. In vitro phenotyping studies suggest that ulotaront is metabolized via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. SEP-383103 is a major but inactive metabolite, and SEP-363854 is a minor active metabolite in humans. The purpose of this population PK analysis was to quantitatively assess the effect of paroxetine, a strong CYP2D6 inhibitor, on the formation and elimination of these two metabolites in healthy subjects.

Description of Methods & Materials: An open label, fixed sequence, Phase 1 study was conducted to investigate the effect of paroxetine on ulotaront PK in healthy subjects with normal CYP2D6 metabolizer status. On Day 1, enrolled subjects received a single oral dose of 25 mg ulotaront. On Day 10, subjects were given a single oral dose of 25 mg ulotaront while paroxetine 20 mg QD was orally administered on Days 5 to 14, allowing paroxetine plasma levels to achieve steady-state. Plasma PK samples were collected over 96 hours after ulotaront dosing on Days 1 and 10. The PK profiles of ulotaront, SEP-383103 and SEP-363854 were compared for each subject when ulotaront was given alone vs when co-administered with paroxetine. A joint population PK model was developed to characterize the PK of ulotaront and its two metabolites and to further assess the impact of CYP2D6 inhibition on ulotaront PK and its metabolism to SEP-383103 and SEP-363854. In addition, this PK model could be used to simulate PK profiles of ulotaront and its metabolites at steady-state in poor or normal CYP2D6 metabolizers.

Data & Results: A total of 24 healthy subjects were enrolled in this study. Twenty-three subjects with plasma concentrations of ulotaront and its two metabolites were used to develop a joint population PK model. In combination with paroxetine, ulotaront C_max and AUC_inf increased by 31% and 72%, respectively, as compared to ulotaront given alone. Co-administration of ulotaront with paroxetine decreased SEP-363854 C_max by 7.3% but increased SEP-363854 AUC_inf by 32%. Paroxetine increased C_max and AUC_inf of SEP-383103 by 18% and 51%, respectively. When incorporating the paroxetine effect in the population PK model, apparent clearance of ulotaront decreased by 40.7%. Apparent clearance of ulotaront to metabolite SEP-383103 decreased by 8.5% for and decreased by 20.4% for metabolite SEP-363854. Apparent clearance of SEP-383103 increased by 1.2%, and apparent clearance of SEP-363854 increased by 2.9%.

Interpretation, Conclusion or Significance: When ulotaront was given with paroxetine, the decrease of apparent clearance of ulotaront was less than 50%. A marginal increase was shown in the formation of these two metabolites, but minor impact on their elimination when CYP2D6 was inhibited in vivo. The modeling results demonstrated the limited impact of a strong CYP2D6 inhibitor on ulotaront PK and its metabolism to SEP-383103 and SEP-363854.

Disclosures: All authors are current employees of Sunovion Pharma or Sumitomo Pharma.