The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: A first in class epothilone B analogue in late-phase clinical development

Sanjay Goel, Marvin Cohen, S. Nilgün Çömezoglu, Lionel Perrin, François André, David Jayabalan, Lisa Lacono, Adriana Comprelli, Van T. Ly, Donglu Zhang, Carrie Xu, W. Griffith Humphreys, Hayley M. McDaid, Gary Goldberg, Susan Band Horwitz, Sridhar Mani

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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/m2 when compared with single-agent therapy of 40 mg/m2. Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC o-∞. 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.

Original languageEnglish (US)
Pages (from-to)2701-2709
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number9
DOIs
StatePublished - May 1 2008

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Ketoconazole
Cytochrome P-450 CYP3A
Pharmacokinetics
Microtubules
Drug Interactions
Cytochrome P-450 Enzyme System
Blood Cells
ixabepilone
epothilone B
Cytochromes
Microsomes
Neutropenia
Area Under Curve
Neutrophils
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone : A first in class epothilone B analogue in late-phase clinical development. / Goel, Sanjay; Cohen, Marvin; Çömezoglu, S. Nilgün; Perrin, Lionel; André, François; Jayabalan, David; Lacono, Lisa; Comprelli, Adriana; Ly, Van T.; Zhang, Donglu; Xu, Carrie; Humphreys, W. Griffith; McDaid, Hayley M.; Goldberg, Gary; Band Horwitz, Susan; Mani, Sridhar.

In: Clinical Cancer Research, Vol. 14, No. 9, 01.05.2008, p. 2701-2709.

Research output: Contribution to journalArticle

Goel, S, Cohen, M, Çömezoglu, SN, Perrin, L, André, F, Jayabalan, D, Lacono, L, Comprelli, A, Ly, VT, Zhang, D, Xu, C, Humphreys, WG, McDaid, HM, Goldberg, G, Band Horwitz, S & Mani, S 2008, 'The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: A first in class epothilone B analogue in late-phase clinical development', Clinical Cancer Research, vol. 14, no. 9, pp. 2701-2709. https://doi.org/10.1158/1078-0432.CCR-07-4151
Goel, Sanjay ; Cohen, Marvin ; Çömezoglu, S. Nilgün ; Perrin, Lionel ; André, François ; Jayabalan, David ; Lacono, Lisa ; Comprelli, Adriana ; Ly, Van T. ; Zhang, Donglu ; Xu, Carrie ; Humphreys, W. Griffith ; McDaid, Hayley M. ; Goldberg, Gary ; Band Horwitz, Susan ; Mani, Sridhar. / The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone : A first in class epothilone B analogue in late-phase clinical development. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 9. pp. 2701-2709.
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abstract = "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/m2 when compared with single-agent therapy of 40 mg/m2. Coadministration of ketoconazole with ixabepilone resulted in a 79{\%} increase in AUC o-∞. 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.",
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AU - Çömezoglu, S. Nilgün

AU - Perrin, Lionel

AU - André, François

AU - Jayabalan, David

AU - Lacono, Lisa

AU - Comprelli, Adriana

AU - Ly, Van T.

AU - Zhang, Donglu

AU - Xu, Carrie

AU - Humphreys, W. Griffith

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