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

Abstract

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.

• Authors: T Kerbusch, R A Mathĵt, H J Keizer, J Ouwerkerk, S Rodenhuis, J H Schellens, J H Beijnen
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 57 Issue 6-7 Pg. 467-77 (Sep 2001) ISSN: 0031-6970 [Print] Germany
• PMID: 11699611 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• dechloroethylcyclophosphamide
• Cyclophosphamide
• 4-hydroxyifosfamide
• dechloroethylifosfamide
• Ifosfamide

Topics

• Adult
• Aged
• Algorithms
• Antineoplastic Agents, Alkylating (pharmacokinetics, therapeutic use, urine)
• Cyclophosphamide (analogs & derivatives, blood, urine)
• Female
• Humans
• Ifosfamide (analogs & derivatives, blood, pharmacokinetics, therapeutic use, urine)
• Infusions, Intravenous
• Male
• Metabolic Clearance Rate
• Middle Aged
• Models, Biological
• Sarcoma (drug therapy, metabolism)