Studies on ifosfamide, a new analogue of cyclophosphamide Part 2, Clinical pharmacology of ifosfamide

A new method for quantitative analysis of ifosfamide and its active metabolite, 4-hydroxy-ifosfamide, was applied to determine the optimal mode of administration of ifosfamide. Three each of six patients with extensive bronchogenic carcinoma were given a single 40mg/kg dose of ifosfamide by either a five-minute or 60-minute intravenous infusion, with a second course of treatment 7-21 days later. Using the NaOH method, the pharmacokinetics was investigated to determine which administration schedule, the five-minute or 60-minute infusion, was preferable for the treatment of clinical malignancies. Ifosfamide was quite stable, but 4-hydroxy-ifosfamide was labile in blood samples, though immediate extraction with dichlorethane minimized the lability of 4-hydroxy-ifosfamide. The distribution volume and the transfer constant into 4-hydroxy-ifosfamide of ifosfamide were rather large, while the transfer constant for urinary excretion was rather small after the 60-minute infusion. The amount of unchanged ifosfamide excreted into urine was larger and its excretion more rapid after the five-minute infusion. As for 4-hydroxy-ifosfamide, the elimination constants and the maximum concentration in the blood were similar for both schedules, but the distribution volume was larger after the 60-minute infusion. The urinary excretion of 4-hydroxy-ifosfamide was delayed and the ratio of 4-hydroxy-ifosfamide to unchanged ifosfamide was larger after the 60-minute infusion. These results suggest that the 60-minute intravenous infusion is preferable to the five-minute intravenous infusion.