Clinical Pharmacokinetics and Pharmacodynamics of Ifosfamide and its Metabolites

Authors: Kerbusch T.¹; de Kraker J.²; Keizer H.J.³; van Putten J.W.G.⁴; Groen H.J.M.⁴; Jansen R.L.H.⁵; Schellens J.H.M.⁶; Beijnen J.H.^{1, 6}

Source: Clinical Pharmacokinetics, Volume 40, Number 1, 2001 , pp. 41-62(22)

Publisher: Adis International

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Abstract:

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways.

Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality of the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment.

Keywords: Antineoplastics, pharmacokinetics; Encephalopathy, drug-induced; Genitourinary disorders, drug-induced; Ifosfamide, adverse reactions; Ifosfamide, pharmacodynamics; Ifosfamide, pharmacokinetics; Kidney disorders, drug-induced

Language: English

Document Type: Review article

Affiliations: 1: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands 2: Department of Paediatric Oncology, Academic Medical Centre, Amsterdam, The Netherlands 3: Department of Clinical Oncology, Leiden University Medical Centre, Leiden, The Netherlands 4: Department of Pulmonary Diseases, University Hospital, Groningen, The Netherlands 5: Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands 6: Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands *

Publication date: 2001-01-01

Clinical Pharmacokinetics and Pharmacodynamics of Ifosfamide and its Metabolites

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