New insights into the pharmacokinetics and metabolism of (R,S)-ifosfamide in cancer patients using a population pharmacokinetic-metabolism model.
OBJECTIVE
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.
Di Marco
M P
MP
Faculté de Pharmacie, Université de Montréal, Canada.
Wainer
I W
IW
Granvil
C L
CL
Batist
G
G
Ducharme
M P
MP
D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007069:Ifosfamide / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007069:Ifosfamide