New insights into the pharmacokinetics and metabolism of (R,S)-ifosfamide in cancer patients using a population pharmacokinetic-metabolism model.

PURPOSE: To describe the pharmacokinetics of R- and S-Ifosfamide (IFF), and their respective 2 and 3 N-dechloroethylated (DCE) metabolites (R2-, R3-, S2, S3-DCE-IFF) in cancer patients.
METHODS: (R,S)-IFF was administered (1.5 g/m2) daily for 5 days in 13 cancer patients. Plasma and urine samples were collected and analyzed using an enantioselective GC-MS method. An average of 97 observations per patient were simultaneously fitted using a pharmacokinetic-metabolism (PK-MB) model. A population PK analysis was performed using an iterative 2-stage method (IT2S).
RESULTS: Auto-induction of IFF metabolism was observed over the 5 day period. Increases were seen in IFF clearance (R: 4 vs. 7 L/h; S: 5 vs. 10 L/h), and in the formation of DCE (R: 7 vs. 9%; S: 14 vs. 19%) and active metabolites (4-OHM-IFF; R: 71 vs. 77%; S: 67 vs. 71%). A novel finding of this analysis was that the renal excretion of the DCE metabolites was also induced.
CONCLUSIONS: This population PK-MB model for (R,S)-IFF may be useful in the optimization of patient care, and gives new insight into the metabolism of (R,S)-IFF.