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

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 0-1 . 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.

CYP3A4-Mediated Ester Cleavage as the Major Metabolic Pathway of the Oral Taxane 3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183)

“…Together with docetaxel, paclitaxel forms the drug category of the taxanes. Taxanes, as well as recently marketed epothilone classes (Goel et al, 2008), stop cell division by inhibition of the microtubule function through stabilizing GDP-bound tubulin in the microtubule. Paclitaxel and docetaxel are administered to patients intravenously because of their poor oral bioavailability.…”

Novel microtubule-targeting agents – the epothilones

“…In humans, co-administration of ketoconazole with ixabepilone increased plasma AUC 0 −∞ (total drug exposure in the plasma) by 79% with a small increase in C p max. In this dose ranging study, the maximum tolerated dose was decreased from 30 mg/m 2 in patients with normal hepatic function to 25 mg/m 2 in the presence of ketoconazole with dose-limiting toxicities of fatigue, neutropenia, mucositis, diarrhea, and febrile neutropenia (Goel et al 2008). In vitro studies indicate that patupilone is a weak inhibitor of CYP2C9, but a phase I study with warfarin did not show signifi cant drug-drug interaction .…”

“…Therefore liver dysfunction may affect clearance of the active drug. There are interpatient variabilities in drug disposition, especially with ixabepilone which is a substrate of cytochrome CYP3A4 (Goel et al 2008). Incubation of ixabepilone in human liver microsomes with different cytochrome inhibitors demonstrated that metabolism of ixabepilone was inhibited by 90% with a potent CYP3A4 inhibitor (ketoconazole).…”

Proactive Management of Adverse Events Maintains the Clinical Benefit of Ixabepilone

“…Ixabepilone is extensively metabolized in the liver via the cytochrome P-450 CYP3A4 isoenzyme [26], and exposure to the drug is greater in patients with pre-existing hepatic impairment, as is common with patients with metastases to the liver, often reflected by significant elevations in liver transaminases (aspartate transaminase [AST] or alanine transaminase [ALT]) or bilirubin [17]. For example, ixabepilone exposure was 22%, 30%, and 83% greater in patients with bilirubin levels Ͼ1ϫ to 1.5ϫ the upper limit of the normal range (ULN), Ͼ1.5ϫ to 3ϫ the ULN, and Ͼ3ϫ the ULN, respectively.…”