In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront, a TAAR1/5-HT1A Receptor Agonist for the Treatment of Schizophrenia.

Abstract

PURPOSE:

Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103.

METHODS:

Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were conducted in vitro. Phenotyping studies were conducted using recombinant human CYPs and FMOs, human liver microsomes and human liver homogenates. Preclinical plasma and brain pharmacokinetics were determined after a single intraperitoneal, intravenous, and oral administration of ulotaront.

RESULTS:

Ulotaront is a compound of high solubility, high permeability, and low binding to plasma proteins. Ulotaront metabolism is mediated via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. Ulotaront is an inducer of CYP2B6, and an inhibitor of CYP2D6, OCT1 and OCT2, while SEP-383103 is neither a CYP inducer nor a potent inhibitor of CYPs and human transporters. Ulotaront exhibits rapid absorption, greater than 70% bioavailability, approximately 3.5 L/kg volume of distribution, 1.5-4 h half-life, 12-43 ml/min/kg clearance, and good penetration across the blood-brain barrier in preclinical species.

CONCLUSIONS:

Ulotaront has been designated as a BCS1 compound by US FDA. The ability of ulotaront to penetrate the blood-brain barrier for CNS targeting has been demonstrated in mice and rats. The potential for ulotaront and SEP-383103 to act as perpetrators of CYP and transporter-mediated DDIs is predicted to be remote.

• Authors: Guangqing Xiao, Yu-Luan Chen, Nina Dedic, Linghong Xie, Kenneth S Koblan, Gerald R Galluppi
• Journal: Pharmaceutical research (Pharm Res) Vol. 39 Issue 5 Pg. 837-850 (May 2022) ISSN: 1573-904X [Electronic] United States
• PMID: 35484370 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Pharmaceutical Preparations
• Receptor, Serotonin, 5-HT1A
• NADP
• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2D6

Topics

• Animals
• Cytochrome P-450 CYP2D6 (metabolism)
• Cytochrome P-450 Enzyme System (metabolism)
• Mice
• Microsomes, Liver (metabolism)
• NADP (metabolism, pharmacology)
• Pharmaceutical Preparations (metabolism)
• Rats
• Receptor, Serotonin, 5-HT1A (metabolism)
• Schizophrenia (drug therapy)