PT  - JOURNAL ARTICLE
AU  - Paola Motta
AU  - Nicoletta Pons
AU  - Sabrina Pagliarusco
AU  - Mario Pellegatti
AU  - Fiorenza Bonomo
TI  - Casopitant: in-vitro data and SimCyp™ simulation to predict in-vivo metabolic interactions involving Cytochrome P450 3A4
AID  - 10.1124/dmd.110.035071
DP  - 2010 Dec 13
TA  - Drug Metabolism and Disposition
PG  - dmd.110.035071
4099  - http://dmd.aspetjournals.org/content/early/2010/12/13/dmd.110.035071.short
4100  - http://dmd.aspetjournals.org/content/early/2010/12/13/dmd.110.035071.full
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.