Clinical and Nonclinical Disposition and In Vitro Drug-Drug Interaction Potential of Felcisetrag, a Highly Selective and Potent 5-HT4 Receptor Agonist

• Published in: European journal of drug metabolism and pharmacokinetics 2022-05, Vol.47 (3), p.371-386
• Main Authors: Pusalkar, Sandeepraj, Chowdhury, Swapan K., Czerniak, Richard, Zhu, Xiaochun, Li, Yuexian, Balani, Suresh K., Ramsden, Diane
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Human Physiology; Medical Biochemistry; Original; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-021-00751-8

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