A Phase I, Open-Label, Fixed Sequence Study to Investigate the Effect of Cytochrome P450 2D6 Inhibition on the Pharmacokinetics of Ulotaront in Healthy Subjects

Ulotaront is a novel psychotropic agent with agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) receptors in phase III clinical development for the treatment of schizophrenia. This study aimed to investigate the effect of paroxetine, a strong cytochrome P450 (CYP) 2D6 inhibitor, on ulotaront pharmacokinetics (PK) in healthy volunteers. Subjects received a single oral dose of 25 mg ulotaront on Day 1 and an oral dose of 20 mg paroxetine once daily from Days 5 to 10 to achieve steady-state plasma paroxetine levels. On Day 11, subjects received another single oral dose of 25 mg ulotaront, with continued daily oral dosing of 20 mg paroxetine from Days 11 to 14. All 24 subjects were CYP2D6 normal metabolizers. Coadministration of paroxetine increased ulotaront maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) by 31% and 72%, respectively, and decreased ulotaront apparent clearance (CL/F) by approximately 42%. While coadministration of paroxetine increased AUC∞ of active but minor metabolite SEP-363854 by 32%, it had no effect on SEP-363854 Cmax, or on SEP-363854 to the ulotaront AUC from time zero to the last quantifiable concentration (AUClast) ratio. Based on the acceptable adverse event profile of ulotaront across previous phase II studies, the increase in ulotaront exposure is unlikely to be clinically meaningful. Weak drug–drug interactions were observed between ulotaront and the strong CYP2D6 inhibitor paroxetine; however, dose adjustment as a precondition when ulotaront is coadministered with strong CYP2D6 inhibitors or administered to CYP2D6 poor metabolizers should not be necessary.