Comparative Bioequivalence of Tablet and Capsule Formulations of Ulotaront and the Effect of Food on the Pharmacokinetics of the Tablet Form in Humans

INTRODUCTION: Ulotaront (SEP-363856), a dual trace animeassociated receptor 1 (TAAR1) and 5-HT(1A) receptor agonist, is in phase 3 clinical development for the treatment of schizophrenia. This study evaluated the comparative bioequivalence (BE) between tablet and capsule formulations of ulotaront and the food effect (FE) on pharmacokinetics (PK) of tablet form in healthy adult human subjects. METHODS: The BE study applied an open-label two-period crossover design in 24 healthy volunteers. Subjects were randomly assigned (1:1) to dosing sequence AB or BA (A, 25 mg ulotaront tablet; B, 25 mg ulotaront capsule). The FE study also used an open-label randomized two-period crossover design in 20 healthy volunteers. Subjects were fasted overnight then randomly assigned (1:1) to dosing sequence AB or BA (A, fasted condition; B, fed condition). Dosing periods were separated by 1 week for both studies. Serial plasma samples from each period were collected and analyzed by LC–MS/MS. PK parameters were calculated using Phoenix WinNonlin(®) software. RESULTS: For the BE study, geometric mean ulotaront C(max) values were 93.28 and 86.98 ng/mL for tablet and capsule, respectively. C(max) ratio was 107.25% (90% CI 101.84–112.94%). Geometric mean ulotaront area under the plasma concentration–time curve from time 0 to infinity (AUC(0–∞)) values were 868.8 and 829.3 ng·h/mL for tablet and capsule, respectively. AUC(0–∞) ratio was 104.76% (90% CI 100.68109.01%). For the FE study, geometric mean ulotaront C(max) was 157.89 and 157.95 ng/mL under fed and fasted conditions, respectively. Geometric mean ratio of C(max) was 99.96% (90% CI 94.48–105.77%). Geometric mean ulotaront AUC(0–∞) was 1584.2 ng·h/mL fed and 1589.2 ng·h/mL fasted. Geometric mean ratio for AUC(0–∞) was 99.69% (90% CI 95.02–104.58%). There was a delay in t(max) (median difference 1.47 h) in the fed condition. CONCLUSIONS: The results showed geometric mean ratios and 90% CIs for both C(max) and AUC(0–∞) for ulotaront were well within typical bioequivalence criteria of 80–125% for both the BE and FE studies, thereby confirming the bioequivalence of the two dosage forms and no significant food effect. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40120-023-00459-8.