title: Casopitant: in vitro data and SimCyp simulation to predict in vivo metabolic interactions involving cytochrome P450 3A4.
abstract: Casopitant [1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S), GW679769] 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. On the basis of this mode of action it was evaluated for the prevention of chemotherapy-induced and postoperative nausea and vomiting, and for the chronic treatment of anxiety, depression, insomnia, and overactive bladder. Casopitant is shown to be a substrate, an inhibitor, and an inducer of CYP3A4, 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. On the basis of the different clinical indications and the various potential comedications 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 evidence of its interaction with CYP3A4 probe substrates midazolam and nifedipine, the strong inhibitor ketoconazole, and the inducer rifampin. Overall, the clinical data confirm the ability of casopitant to interact with CYP3A4 substrates, inhibitors, or inducers. The in vitro data are accurate and robust enough to build a reliable SimCyp population-based model to estimate the potential DDIs of casopitant and to minimize the clinical studies recommended.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Medicine Research Center, GlaxoSmithKline, Verona, Italy. paola.motta@aptuit.com
authors.forename: Paola
authors.initials: P
authors.lastname: Motta
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pons
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pagliarusco
authors.forename: Mario
authors.initials: M
authors.lastname: Pellegatti
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Bonomo
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D008958:Models, Molecular; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010879:Piperazines / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010880:Piperidines / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult; D014508:Urea
chemical_list: D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents; D010879:Piperazines; D010880:Piperidines; D011994:Recombinant Proteins; C558658:GSK 525060; C531951:casopitant; D014508:Urea; C510163:CYP3A4 protein, human