Clinical and Nonclinical Disposition and In Vitro Drug-Drug Interaction Potential of Felcisetrag, a Highly Selective and Potent 5-HT(4) Receptor Agonist

BACKGROUND AND OBJECTIVE: Felcisetrag (previously TAK-954 or TD-8954) is a highly selective and potent 5-HT(4) receptor agonist in clinical development for prophylaxis and treatment of postoperative gastrointestinal dysfunction (POGD). The rat, dog, and human absorption, distribution, metabolism, and excretion (ADME) properties of felcisetrag were investigated. METHODS: The metabolism and victim and perpetrator drug interaction potentials towards cytochrome P450s (CYP) and transporters were determined using in vitro models. The excretion, metabolite profile, and pharmacokinetics were determined during unlabeled and radiolabeled ADME studies in rat and dog for comparison with human. Due to a low clinical dose (0.5 mg) and radioactivity (~ 1.5 μCi), a combination of liquid scintillation counting and accelerator mass spectrometry was used for analysis of samples in this study. RESULTS: The ADME properties, including metabolite profile, for felcisetrag are generally conserved across species. Felcisetrag is primarily cleared through renal excretion (0.443) and metabolism in humans (0.420), with intact parent as the predominant species in circulation. There are multiple metabolites, each representing < 10% of the circulating radioactivity, confirming no metabolites in safety testing (MIST) liabilities. Metabolites were also detected in animals. The potential for major CYP- and transporter-based drug–drug interaction (DDI) of felcisetrag as a victim or perpetrator is considered to be low. CONCLUSIONS: Felcisetrag is primarily cleared in humans through renal excretion. Although the metabolism of felcisetrag is primarily through CYP3A, the potential for clinically relevant DDI as a victim is significantly reduced as metabolism plays a minor role in the overall clearance. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13318-021-00751-8.