Evaluation of OCT2 ‐mediated drug–drug interactions between ulotaront and metformin in subjects with schizophrenia

Plasma and urine pharmacokinetic parameters of metformin along and in combination with ulotaront. AbstractUlotaront (SEP-363856) is a TAAR1 agonist, with 5-HT1A agonist activity, currently in clinical development for the treatment of schizophrenia. In  vitro studies indicate ulotaront is an OCT2-specific inhibitor with IC50 of 1.27  μM. The primary objective of this study is to determine if a single dose of ulotaront affects the PK of metformin, an index substrate of OCT2, in subjects with schizophrenia. In a randomized, single-blind, 2-period crossover study, 25 adults with schizophrenia received a single dose of metformin -HCl 850 mg (approximately 663 mg metformin) with and without coadministration of 100 mg ulotaront. The plasma samples were analyzed by fully validated LC–MS/MS methods. The primary PK endpoints for metformin were AUCinf, AUClast,Cmax, andtmax. The highest-anticipated clinical dose of ulotaront (100  mg) had no statistically significant effect on the PK of a single dose of metformin based onCmax and AUCinf. Geometric least squares mean ratios were 89.98% and 110.63%, respectively, with the 90% confidential interval (CI) for each parameter contained within 80% –125%. Mediantmax was comparable across the treatments. Ulotaront does not act as a perpetrator of OCT2-mediated DDI against metformin. Co-administration of ulotaront is not expected to require dose adjustment of metformin or other drugs cleared by OCT2.
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research