Pharmacokinetics of ifosfamide are changed by combination with docetaxel -Results of a phase I pharmacologic study

The pharmacokinetics of the combination of docetaxel and ifosfamide were st udied in a phase I study. Docetaxel was given to cancer patients as a 1-hou r infusion followed by a 24-hour infusion of ifosfamide (schedule A). After the dose-limiting toxicity of the combination was reached, ifosfamide was administered as a 24-hour infusion followed after 24 hours by a 1-hour infu sion of docetaxel (schedule B). Cycle duration was 21 days. Docetaxel was d etermined by high-performance liquid chromatography, and ifosfamide and its metabolites, by gas chromatography-mass spectrometry. Twenty-seven patient s were treated according to schedule A, and 6 according to schedule B. Comb ining the two drugs did not change their respective plasma half-lives. The sequence of drug administration did not affect the clearance and the area u nder the curve (AUC) of docetaxel. There was a decrease in the AUC of ifosf amide in schedule A compared with schedule B, resulting from an increase in the clearance of ifosfamide. The pharmacokinetics of docetaxel are not inf luenced by combination with ifosfamide, regardless of the drug sequence, bu t ifosfamide pharmacokinetics are changed by docetaxel, depending on the se quence of administration. The increase of clearance in schedule A may be du e to the pretreatment with corticosteroids.