The Effect of Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Ixabepilone: A First in Class Epothilone B Analogue in Late-Phase Clinical Development

• Published in: Clinical cancer research 2008-05, Vol.14 (9), p.2701-2709
• Main Authors: Goel, Sanjay, Cohen, Marvin, Cömezoglu, S Nilgün, Perrin, Lionel, André, François, Jayabalan, David, Iacono, Lisa, Comprelli, Adriana, Ly, Van T, Zhang, Donglu, Xu, Carrie, Humphreys, W Griffith, McDaid, Hayley, Goldberg, Gary, Horwitz, Susan B, Mani, Sridhar
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; BMS-247550; Chemical Sciences; Computational Biology; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; epothilones; Epothilones - administration & dosage; Epothilones - adverse effects; Epothilones - pharmacokinetics; Epothilones - pharmacology; Female; Genital Neoplasms, Female - drug therapy; Genital Neoplasms, Female - metabolism; Humans; ixabepilone; Ketoconazole; Ketoconazole - administration & dosage; Ketoconazole - adverse effects; Ketoconazole - pharmacology; Leukocytes, Mononuclear - metabolism; Liver - metabolism; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Male; Medicinal Chemistry; Microsomes, Liver - metabolism; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; pharmacokinetics; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Tubulin Modulators - administration & dosage; Tubulin Modulators - adverse effects; Tubulin Modulators - pharmacokinetics; Tubulin Modulators - pharmacology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4151

Purpose: To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4. Experimental Design: Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone. Results: Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m 2 when compared with single-agent therapy of 40 mg/m 2 . Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC 0-∞ . The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia. Conclusions: Ixabepilone is a good CYP3A4 substrate in vitro ; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.