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Research ArticleArticle

Casopitant: In Vitro Data and SimCyp Simulation to Predict In Vivo Metabolic Interactions Involving Cytochrome P450 3A4

Paola Motta, Nicoletta Pons, Sabrina Pagliarusco, Mario Pellegatti and Fiorenza Bonomo
Drug Metabolism and Disposition March 2011, 39 (3) 363-372; DOI: https://doi.org/10.1124/dmd.110.035071
Paola Motta
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Nicoletta Pons
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Sabrina Pagliarusco
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Mario Pellegatti
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Fiorenza Bonomo
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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.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035071.

  • ABBREVIATIONS:

    DDI
    drug-drug interaction
    P450
    cytochrome P450
    GW679769
    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)
    MID
    midazolam
    NIF
    nifedipine
    KET
    ketoconazole
    RIF
    rifampin
    FDA
    U.S. Food and Drug Administration
    GSK
    GlaxoSmithKline
    TAO
    troleandomycin
    HLM
    human liver microsomes
    6βT
    6β-hydroxy testosterone
    HPLC
    high-performance liquid chromatography
    MS/MS
    tandem mass spectroscopy
    AUC
    area under the plasma concentration-time curve.

  • Received June 22, 2010.
  • Accepted December 13, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (3)
Drug Metabolism and Disposition
Vol. 39, Issue 3
1 Mar 2011
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Research ArticleArticle

Casopitant: In Vitro Data and SimCyp Simulation to Predict In Vivo Metabolic Interactions Involving Cytochrome P450 3A4

Paola Motta, Nicoletta Pons, Sabrina Pagliarusco, Mario Pellegatti and Fiorenza Bonomo
Drug Metabolism and Disposition March 1, 2011, 39 (3) 363-372; DOI: https://doi.org/10.1124/dmd.110.035071

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Research ArticleArticle

Casopitant: In Vitro Data and SimCyp Simulation to Predict In Vivo Metabolic Interactions Involving Cytochrome P450 3A4

Paola Motta, Nicoletta Pons, Sabrina Pagliarusco, Mario Pellegatti and Fiorenza Bonomo
Drug Metabolism and Disposition March 1, 2011, 39 (3) 363-372; DOI: https://doi.org/10.1124/dmd.110.035071
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