What is already known about this subject: * The optimal infusion duration for ifosfamide remains to be determined. * No differences according to time of infusion have been identified in traditional pharmacokinetic endpoints, such as area under the curve. * The impact on pharmacodynamics has never been modelled or correlated with pharmacokinetics.
What this study adds: * The pharmacokinetics and pharmacodynamics of ifosfamide and its main metabolites can both be modelled with no influence of infusion duration. * Pharmacodynamic modelling (renal and haematological toxicity) allows further simulations of new schedules with favourable toxicity profiles.
Aims: To model the pharmacokinetics and pharmacodynamics of ifosfamide and its key metabolites. The pharmacodynamic parameters included were renal toxicity and myelosuppression measured using urinary beta(2)-microglobulin (BMG) and absolute neutrophil count (ANC), respectively.
Methods: Seventeen patients were enrolled into an n = 1 randomized trial during two consecutive cycles of ifosfamide 9 g m(-2) during each cycle given by a 3 h or 72 h infusion. Data were analyzed using NONMEM.
Results: Ifosfamide and metabolite concentration-time profiles were described by a one-compartment open-model with auto-induction of clearance. BMG and ANC time-courses were related to ifosfamide concentration via indirect response models.
Conclusions: This modelling allowed the simulation of weekly schedules of flat doses with favourable myelotoxic profiles.