Assessment of ifosfamide pharmacokinetics, toxicity, and relation to CYP3A4 activity as measured by the erythromycin breath test in patients with sarcoma

Abstract

Background: Ifosfamide is a chemotherapeutic agent that requires cytochrome P450 3A (CYP3A) for bioactivation and metabolism. To the authors' knowledge, the correlation between dose, pharmacokinetics, CYP3A, and toxicity has not been fully evaluated. A randomized Phase II trial was performed on 22 soft tissue sarcoma patients treated with doxorubicin (60 mg/m(2)/cycle) and either high-dose ifosfamide (12 g/m(2)/cycle) or standard-dose ifosfamide (6 g/m(2)/cycle). The pharmacokinetics of ifosfamide and CYP3A measurements observed are reported.

Methods: Pharmacokinetic parameters for ifosfamide, 2-dichloroethylifosfamide (2-DCE), and 3-dichloroethylifosfamide (3-DCE) were collected after the first ifosfamide infusion in 13 patients. Bayesian designed limited pharmacokinetic data were collected from an additional 41 patients. The erythromycin breath test (ERMBT) was performed on 81 patients as an in vivo phenotypic assessment of CYP3A activity.

Results: Fourteen-hour (peak) plasma levels of ifosfamide, 2-DCE, and 3-DCE were found to correlate strongly with the respective area under the curve (AUC) 0-24 values (r=0.97, 0.94, and 0.95; P<.0001). Patients who experienced a grade 3-4 absolute neutrophil count (ANC), platelet, or creatinine toxicity (using the National Cancer Institute Common Toxicity Criteria [version 2]) were found to have statistically significantly higher median 14-hour plasma levels of ifosfamide, 2-DCE, and 3-DCE compared with patients with grade 0-2 toxicity. ERMBT was not found to correlate with pharmacokinetic parameters of ifosfamide and metabolites or toxicity.

Conclusions: The 14-hour plasma level of ifosfamide, 2-DCE, and 3-DCE is a simple and appropriate substitute for describing the AUC of ifosfamide after 1 day of a 1-hour to 2-hour infusion of drug. Fourteen-hour plasma levels of ifosfamide and metabolites are useful predictors of neutropenia, thrombocytopenia, and creatinine toxicity. ERMBT was not found to accurately correlate with ifosfamide pharmacokinetics or clinical toxicity.