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

OBJECTIVE: The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma. METHODS: Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling. RESULTS: The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. 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 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.