Population pharmacokinetics and exploratory pharmacodynamics of ifosfamideand metabolites after a 72-h continuous infusion in patients with soft tissue sarcoma

Objective: The population pharmacokinetics and pharmacodynamics of the cyto static agent ifosfamide and its main metabolites 2- and 3-dechloroethylifos famide and 4-hydroxyifosfamide were assessed in patients with soft tissue s arcoma. Methods: Twenty patients received 9 or 12 g/m(2) ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic mod el was built in a sequential manner, starting with a covariate-free model a nd progressing to a covariate model with the aid of generalised additive mo delling. Results: The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogena se improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 1/h with a volum e of distribution of 44.0 +/- 1.81. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 muM ifosfamide. Significant pharmacok inetic-pharmacodynamic relationships (P=0.019) were observed between the ex posure to 2- and 3-dechloroethylifosfamide and orientational disorder, a ne urotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships betw een exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.