Pharmacokinetic modelling of ifosfamide administered by continuous infusion on 5 days at the dose of 6 g/m2
Passe, P.; Delepine, N.; Arnaud, P.; Urien, S.; Delepine, G.; Traoré, F.; Desbois, J.C.; Brion, F.
Anticancer Research 19(1B): 837-842
1999
ISSN/ISBN: 0250-7005 PMID: 10216502 Document Number: 503972
Background. We aimed to create a model for Ifosfamide (IFX) pharmacokinetics for drug monitoring in order to improve protocol dose intensity. Material and 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. Conclusion: Levy's model is more accurate and takes into account the integration of clearance.