Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8 to 5.0 g/m2, the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6 to 2.4 g/m2/day, the plasma decay is monoexponential and the terminal elimination half-life is about 7 hours.

Ifosfamide exhibits time-dependent pharmacokinetics in humans. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, a decrease in the median elimination half-life from 7.2 hour on Day 1 to 4.6 hours on Day 5 occurred with a concomitant increase in the median clearance from 66 mL/min on Day 1 to 115 mL/min on Day 5. There was no significant change in the volume of distribution on Day 5 compared with Day 1.

Distribution

Ifosfamide volume of distribution (Vd) approximates the total body water volume, suggesting that distribution takes place with minimal tissue binding. Following intravenous administration of 1.5 g/m2 over 0.5 hour once daily for 5 days to 15 patients with neoplastic disease, the median Vd of ifosfamide was 0.64 L/kg on Day 1 and 0.72 L/kg on Day 5. Ifosfamide shows little plasma protein binding. Ifosfamide and its active metabolites are extensively bound by red blood cells. Ifosfamide is not a substrate for P-glycoprotein.

Metabolism

Ifosfamide is extensively metabolized in humans through two metabolic pathways: ring oxidation (“activation”) to form the active metabolite, 4-hydroxy-ifosfamide and side-chain oxidation to form the inactive metabolites, 3-dechloro-ethylifosfamide or 2-dechloroethylifosfamide with liberation of the toxic metabolite, chloroacetaldehyde. Small quantities (nmol/mL) of ifosfamide mustard and 4‑hydroxyifosfamide are detectable in human plasma. Metabolism of ifosfamide is required for the generation of the biologically active species and while metabolism is extensive, it is also quite variable among patients.

Excretion

After administration of doses of 5 g/m2 of 14C-labeled ifosfamide, from 70% to 86% of the dosed radioactivity was recovered in urine as metabolites, with about 61% of the dose excreted as parent compound. At doses of 1.6 to 2.4 g/m2 only 12% to 18% of the dose was excreted in the urine as unchanged drug within 72 hours. Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4‑hydroxyifosfamide and acrolein are present. 

Pediatrics

Population PK analysis was performed on plasma data from 32 pediatric patients various malignant diseases aged between 1 and 18 years. Patients received a total of 45 courses of ifosfamide at doses of 1.2, 2.0 and 3.0 g/m2 given intravenously over 1 or 3 hours on 1, 2, or 3 days. The mean±standard error population estimates for the initial clearance and volume of distribution of ifosfamide were 2.4±0.33 L/h/m2 and 21±1.6 L/m2 with an interindividual variability of 43% and 32%, respectively.

Effect of Age

A study of 20 patients between 40 to 71 years of age receiving 1.5 g/m2 of ifosfamide daily for 3 or 5 days indicated that elimination half‑life appears to increase with age. The elimination half‑life increase appeared to be related to the increase in ifosfamide volume of distribution with age. No significant changes in total plasma clearance or renal clearance with age were reported.