Toxicity, pharmacokinetics, and in vitro hemodialysis clearance of ifosfamide and metabolites in an anephric pediatric patient with Wilms' tumor

Abstract

Purpose: We evaluated the in vitro hemodialysis ratio and subsequent toxicity and pharmacokinetics of ifosfamide in an anephric patient with Wilms' tumor. Methods: An in vitro model was used to determine the extraction ratio of ifosfamide by dialysis. The toxicity and plasma concentrations of ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide were then determined over 24 h after a single 1.6 g/m² dose of ifosfamide. Plasma concentrations were also measured before and after ten dialysis sessions during four courses of ifosfamide therapy. Results: The in vitro hemodialysis model showed that ifosfamide was cleared with an extraction ratio of 86.7 ± 0.5% and remained constant even at low concentrations of drug. The mean decrease in vivo following hemodialysis for ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide were 86.9%, 77.2%, and 36.2%, respectively. The pharmacokinetic parameters for ifosfamide using model-independent methods were calculated: Vd = 0.23 l/kg, t_½ = 4.8 h, and Cl_T = 3.30 l/h per m². Ifosfamide-associated neurotoxicity was noted within hours of drug administration and improved rapidly following hemodialysis. Conclusions: The results of our study suggest that the pharmacokinetics of parent ifosfamide may not be substantially altered in patients with renal failure. Hemodialysis was shown to remove ifosfamide, chloroacetaldehyde, and 4-hydroxyifosfamide from the blood stream. Hemodialysis was also shown to reverse ifosfamide-related neurotoxicity.