IFOSFAMIDE NEPHROTOXICITY - LIMITED INFLUENCE OF METABOLISM AND MODE OF ADMINISTRATION DURING REPEATED THERAPY IN PEDIATRICS

This study investigated the relationship between both acute and chroni c nephrotoxic effects of ifosfamide (IFO) and its metabolism. 15 paedi atric patients (4 girls) were investigated. Each received 6-9 g/m(2) I FO over 15 days, repeated every 3 weeks for up to 16 courses. The phar macokinetics and metabolism of IFO were measured during its administra tion, either as a continuous 72 h infusion or as three bolus doses of 3 g/m(2) on consecutive days. In 8 patients, the metabolism of IFO was investigated during one early course and one late course to determine the magnitude of any changes following repeated administration. Acute measures of renal toxicity were not correlated with any of the IFO ph armacokinetic or metabolic parameters in the same course, whether the drug was administered as a bolus or by continuous infusion. Chronic re nal toxicity, determined 1 month (n = 13) or 6 months (n = 8) after tr eatment, did not correlate with any of the IFO pharmacokinetic or meta bolic parameters in any individual course of treatment. The overall de gree of nephrotoxicity, however, was correlated with the changes in me tabolism between late and early courses (n = 8). There was a negative correlation between the change in area under the curve of the dechloro ethylated metabolites of IFO and the overall nephrotoxicity at 1 month or 6 months after treatment (both r(2) = 0.66, P = 0.014). The result s imply that patients in whom metabolism via dechloroethylation decrea ses are at a greater risk of chronic nephrotoxicity. This is contrary to the hypothesis that the systemic production of chloroacetaldehyde i s the mechanism by which IFO causes nephrotoxicity. The importance of acute and chronic changes in renal function for long-term outcome rema ins to be determined. Copyright (C) 1996 Elsevier Science Ltd