A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles

1. Ifosfamide demonstrates increased clearance with time when administered daily for 5 days. The objectives of this study were to define whether the increased ifosfamide clearance was sustained between treatment cycles and whether it was reproducible in consecutive treatment cycles. 2. Seven patients with inoperable cancer received 1.5 g m-2 ifosfamide infused intravenously over 0.5 h, each day for 5 days, for two consecutive cycles. Urine and appropriately timed blood samples were collected for up to 24 h post ifosfamide infusion on day 1 and day 5. Plasma ifosfamide concentrations were assayed by gas liquid chromatography and pharmacokinetic parameters were imputed using non-compartmental analysis. 3. The difference in the mean (n = 7) total ifosfamide plasma clearance between day 5 and day 1 of Cycle I was an increase of 56.8 ml min-1 (99.8% CIs + 22.6-->+ 91.4). The difference in the mean (n = 7) total ifosfamide plasma clearance between day 1 of Cycle II and day 5 was a decrease of 61.9 ml min-1 (99.8% CIs -111.2 -->-12.6). The magnitude of the mean increase in total ifosfamide plasma clearance in Cycle II and Cycle I was similar because the difference between these means (0.9 ml min-1, 99.8% CIs -63.7-->+65.3) was not statistically significant. There was no change in the apparent volume of distribution of ifosfamide between the two study days in either of Cycle I or II, or between cycles. 4. The difference in the mean (n = 7) ifosfamide renal clearance between day 5 and day 1 of Cycle I was minus 0.4 ml min-1 (99.8% CIs -8.5-->+8.6); the means +/- s.d. wee 6.3 +/- 2.6 ml min-1 and 6.7 +/- 3.2 ml min-1 respectively. The difference in the mean (n = 4) ifosfamide renal clearance between day 5 and day 1 of Cycle II was -0.2 ml min-1 (99.8% CIs -5.7-->+5.2); the means +/- s.d. were 7.8 +/- 6.1 ml min-1 and 8.0 +/- 6.2 ml min-1 respectively. 5. These data suggest that the increase in total ifosfamide plasma clearance with time in a 5 day fractionated regimen was due to an increase in ifosfamide metabolism which was not sustained over the 21 days between cycles, but was reproducible and of a similar magnitude in the two consecutive treatment cycles studied.