RT Journal Article SR Electronic T1 Casopitant: in-vitro data and SimCyp™ simulation to predict in-vivo metabolic interactions involving Cytochrome P450 3A4 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.110.035071 DO 10.1124/dmd.110.035071 A1 Paola Motta A1 Nicoletta Pons A1 Sabrina Pagliarusco A1 Mario Pellegatti A1 Fiorenza Bonomo YR 2010 UL http://dmd.aspetjournals.org/content/early/2010/12/13/dmd.110.035071.abstract AB Casopitant has previously been shown to be a potent and selective antagonist of the human neurokinin-1 receptor, the primary receptor of substance P, both in vitro and in vivo, with good brain penetration properties. Based on this mode of action it was evaluated for the prevention of chemotherapy-induced and post-operative nausea and vomiting, and for the chronic treatment of anxiety, depression, insomnia, and over-active bladder. Casopitant is shown to be a substrate, an inhibitor and an inducer of cytochrome P450 (CYP) 3A4 and, because of this complex behavior, it was difficult to identify the primary mechanism by which it may give rise to drug-drug interactions (DDIs) of clinical relevance. Moreover, the major circulating metabolite is itself an inhibitor of CYP3A4 in vitro. Based on the different clinical indications and the various potential co-medications of casopitant, a relevant part of the clinical development plan was focused on the assessment of the importance of clinical DDIs. The present study provides an overview of the DDI potential profile of casopitant, based on in vitro data and clinical evidences of its interaction with CYP3A4 probe substrates midazolam (MID) and nifedipine (NIF), the strong inhibitor ketoconazole (KET) and the inducer rifampin (RIF). Overall, the clinical data confirm the ability of casopitant to interact with CYP3A4 substrates, inhibitors or inducers. The in vitro data are enough accurate and robust to build a reliable SimCyp™ population-based model, so as to estimate the potential DDI of casopitant and to minimize the clinical studies recommended.