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

• Published in: Pharmaceutical research Vol. 17; no. 6; pp. 645 - 652
• Main Authors: DI MARCO, M. P, WAINER, I. W, GRANVIL, C. L, BATIST, G, DUCHARME, M. P
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.06.2000; Springer Nature B.V
• Subjects: Antineoplastic agents; Antineoplastic Agents, Alkylating - metabolism; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - therapeutic use; Aryl Hydrocarbon Hydroxylases; Biological and medical sciences; Cancer; Chemotherapy; Chromatography; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Drug dosages; Enzymes; General pharmacology; Humans; Ifosfamide - metabolism; Ifosfamide - pharmacokinetics; Ifosfamide - therapeutic use; Medical sciences; Metabolism; Metabolites; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - urine; Oxidoreductases, N-Demethylating - metabolism; Patients; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Plasma; Urine; Antineoplastic agent; Human; Urine; Biological fluid; Intravenous administration; Ifosfamide; Metabolite; Estimation; Malignant tumor; Metabolism; Modeling; Blood plasma; Chemotherapy; Oxazaphosphinane derivatives; Treatment; Nitrogen mustard; Pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1007561727948

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. (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). 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. 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.