epothilone-a and Genital-Neoplasms--Female

Ixabepilone is a semisynthetic analogue of epothilone B, a novel microtubule-stabilizing agent. Preclinical data suggest that its mechanisms of actions are different from those of the most commonly used microtubule-stabilizing agent, paclitaxel. This information in addition to the cytotoxicity of this drug in taxane-resistant cell lines in multiple solid tumors supports the fact that ixabepilone may be active in taxane-resistant tumors. Breast and gynecologic malignancies are leading causes of morbidity and mortality in women. Clinical studies demonstrate significant activity of ixabepilone monotherapy in these heavily pretreated patients. The toxicity profile of ixabepilone seems to be similar to that of taxanes and manageable by supportive methods.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epothilones; Female; Genital Neoplasms, Female; Humans

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.. 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.. 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.. 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.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Computational Biology; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Epothilones; Female; Genital Neoplasms, Female; Humans; Ketoconazole; Leukocytes, Mononuclear; Liver; Liver Neoplasms; Male; Microsomes, Liver; Middle Aged; Neoplasms; Prostatic Neoplasms; Tubulin Modulators