The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development.
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Goel S, Cohen M, Comezoglu SN, Perrin L, Andre F, Jayabalan D, Iacono L, Comprelli A, Ly VT, Zhang D, Xu C, Humphreys WG, McDaid H, Goldberg G, Horwitz SB, Mani S
The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of ixabepilone: a first in class epothilone B analogue in late-phase clinical development.
Clin Cancer Res. 2008 May 1;14(9):2701-9. doi: 10.1158/1078-0432.CCR-07-4151.
- PubMed ID
- 18451235 [ View in PubMed]
- 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/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-infinity). 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Ixabepilone Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareIxabepilonePhenytoin The metabolism of Ixabepilone can be increased when combined with Phenytoin. IxabepilonePentobarbital The metabolism of Ixabepilone can be increased when combined with Pentobarbital. IxabepiloneMitotane The metabolism of Ixabepilone can be increased when combined with Mitotane. IxabepilonePrimidone The metabolism of Ixabepilone can be increased when combined with Primidone. IxabepiloneRifampicin The metabolism of Ixabepilone can be increased when combined with Rifampicin.