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

Abstract

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. were 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.

Population pharmacokinetics of doxorubicin, etoposide and ifosfamide in small cell lung cancer patients: results of a multicentre study

“…on 3–5 consecutive days [19]. It was also described with shorter infusions, as in this study [22–24] but these studies did not include models which structurally incorporated auto‐induction. Very low correlation coefficients demonstrate the lack of relationship between the main PK parameters of the three component drugs of the AVI regimen.…”

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

“…(31)) and ifosfamide metabolism has been observed within 12 to 24 hr after the start of treatment. Auto-induction is typically observed between day 1 to day 5, but metabolic rates are always reset to initial base level at the start of a consecutive course 3 weeks later [1309]. Cyclophospahmide has been shown to induce CYP2C9 and 3A4 expression in a concentration-dependent manner in cultured primary human hepatocytes [1310][1311][1312].…”

The Pharmacologic Basis of Ifosfamide Use in Adult Patients with Advanced Soft Tissue Sarcomas

“…Autoinduction of ifosfamide has been described to occur within 12-24 hours after the start of treatment. Importantly, metabolic rates return to initial levels within 3 weeks [34]. Autoinduction of ifosfamide metabolism seems to be influenced by dose and dosing schedule.…”