Pharmacokinetic modelling of ifosfamide administered by continuous infusion on 5 days at the dose of 6 g/m2.
BACKGROUND
We aimed to create a model for Ifosfamide (IFX) pharmacokinetics for drug monitoring in order to improve protocol dose intensity.


METHODS
We studied ifosfamide pharmacokinetics in 12 patients aged 8-19 years. Sixteen courses were modelled (6 g/m2, on 5 days). The auto-induction of ifosfamide was taken into account in the model. Ifosfamide measurement was performed on serum samples by gas chromatography with thermo-ionic detection. Two pharmacokinetic models were compared. The following parameters were estimated: volume of distribution (Vd), clearance at the beginning of the induction (CLi), clearance extrapolated to infinity (CLf), clearance at the end of infusion (CL120), a rate constant (Kc) indicating the clearance variation with time and the lag time (Lag) indicating the time elapsed between the start of infusion and the start of induction. The Wilcoxon test was used to investigate possible differences between models. We tested the hypothesis that Boddy's model is an acceptable simplification of Levy's model.


RESULTS
Four of six parameters were significantly different between the two models (p = 0.05). The best curve fitting was obtained using the Levy's model which provided the following estimates, Cli = 2.46 +/- 0.94 L.h-1.m-2, CLf = 5.22 +/- 1.02 L.h-1.m-2, Kc = 0.024 +/- 0.014 h-1, Vd = 18.84 +/- 5.04 L and Lag = 4.86 +/- 6.61 h. The most important difference is found for the distribution volume.


CONCLUSIONS
Levy's model is more accurate and takes into account the integration of clearance.
Passe
P
P
Pharmacy and Toxico-Pharmacological Laboratory of University Hospital Robert Debré, Paris, France.
Delepine
N
N
Arnaud
P
P
Urien
S
S
Delepine
G
G
Traoré
F
F
Desbois
J C
JC
Brion
F
F
D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001859:Bone Neoplasms / Q000188:drug therapy; D002648:Child; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000493:pharmacokinetics*; D008297:Male; D008433:Mathematics; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D012509:Sarcoma / Q000188:drug therapy; D012983:Soft Tissue Neoplasms / Q000188:drug therapy
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide