PHARMACOKINETICS AND METABOLISM OF IFOSFAMIDE ADMINISTERED AS A CONTINUOUS-INFUSION IN CHILDREN

The pharmacokinetics and metabolism of ifosfamide was investigated in a group of 16 pediatric patients (5 girls) aged 1-17 years. Each recei ved a dose of 3 g/m2/day for up to 3 days by continuous infusion. Plas ma and urine were collected, and concentrations of ifosfamide and its principal metabolites were determined by a quantitative high-performan ce thin layer chromatography method. During 3 days of continuous infus ion, the plasma concentrations of parent drug decreased. This was acco mpanied by a continuous increase in dechloroethylated products in plas ma but not in urine. Estimated pharmacokinetic parameters (clearance, volume of distribution, and half-life) were dependent on body size and age but not any other patient variable. Renal clearance was a relativ ely minor route of elimination for parent drug and corresponded to <25 % of glomerular filtration rate. Metabolite data from plasma and urine indicated a high degree of interindividual variation in metabolism. C omparison of metabolite recoveries in urine indicated a positive corre lation between activation and inactivation routes of metabolism. Prior exposure to ifosfamide was associated with a higher recovery in urine of dechloroethylated metabolites. The severity of hematological toxic ity was inversely correlated with glomerular filtration rate but not t o parameters of ifosfamide metabolism. There was marked variation in l evels of the carboxy metabolite, which could not be detected in the pl asma of 5 subjects. However, evidence for a polymorphism in metabolism to this metabolite was weaker than that seen with the isomeric oxazap hosphorine cyclophosphamide. There appeared to be a higher clearance o f ifosfamide in pediatric patients compared to adults. The significanc e of this, and of the variation in metabolism of ifosfamide, for clini cal outcome remains to be established, but the increase in the dechlor oethylation route of metabolism may be associated with an increased ri sk of toxicity.