Ifosfamide in continuous infusion: the pharmacokinetic profile in patients with soft tissue sarcomas

Ifosfamide, an oxazophosphorin compound, active in mesenchimal tumours has recently been used at high doses (14–18 g/sqm) in order to increase the number of responses. Continuous infusion (C.L) of Ifosfamide probably decreases toxicity and increases the therapeutic window of the drug. Bone marrow and renal toxicities seem to be modified greatly by C.L.. Aim of our study has been to characterize the pharmacokinetic drug profile during C.L high dose-fosfamide (HD-IFO). From April to December 1994, 9 patients (pts) with advanced soft tissue sarcomas, 5 pts with osteosarcomas and I pts with Ewing's sarcoma with normal liver and renal function, treated with C.I. HD-IFO (14 g/sqm. over 4 days) and Mesna contemporary infusion, entered into the study. 33 chemotherapy courses were administered (range 1–4, mean 2.2). Pts were submitted to blood sampling previous starting of infusion, and 12, 24,48,72,96, 100, 104, 114, and 120 hours after treatment beginning. Plasma samples were stored at 0°C. Chemical analysis was perfonned using HPLC. Maximum concentration of the drug was observed at 24th hour ( C 24 : 61.5 ± 21.9/μg/ml) while decreased pseudo-steady rate levels were reached after 70–80 hours ( C ss: 28.3 ± 11.5 μg/ml). Tenninal half life was 3.2 ± 0.4 hours; AVC (following trapezoidal rule) was 3654 ± 1222 mg/l. × hour. Median Clearances (total dose/AVC) was 7.14 ± 3.31/h. At the second or following cycles a relevant reduction of Tl/2 and AVC (–20% and –25%) due to enzymatic auto induction was observed. In confront with Ifosfamide administration at the same doses but in 1 hour infusion we observed that C.I. leads to a higher AUC (3650 vs. 1230) to a shorter Tl/2 (3.2 h. vs. 5.9 h.) and to a relevant increase of total clearance (7.14 vs. 3.9). This significant difference in pharmacokinetic profile can explain the different spectrum of activity between the two manners of administration.