Clinical pharmacokinetics of amifostine and WR1065 in pediatric patients with medulloblastoma.

Abstract

We evaluated the pharmacokinetics of amifostine and WR1065 in pediatric patients with newly diagnosed medulloblastoma to assess the influence of patient covariates, including demographics, clinical characteristics, and genetic polymorphisms, on amifostine and WR1065 pharmacokinetic parameters. We assessed the pharmacokinetics of amifostine and WR1065 in 33 children who received amifostine (1-minute infusion, 600 mg/m(2)) just before the start of and 3 hours into a 6-hour cisplatin infusion. Serial blood samples were collected after doses 1 (0 hour) and 2 (3 hours) of course 1. Amifostine and WR1065 were quantitated by high performance liquid chromatography with electrochemical detection. A pharmacokinetic model was simultaneously fit to amifostine and WR1065 plasma or whole blood concentration-versus-time data. The influence of demographic, biochemical, and pharmacogenetic covariates on amifostine and WR1065 disposition was evaluated. Body surface area was the primary size-based covariate for amifostine pharmacokinetics explaining 53% and 56% of interindividual variability in plasma and whole-blood amifostine clearance, respectively. The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from the plasma data were 107 L/h/m(2), 5.53 L/m(2), and 30.6 L/h/m(2). The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from whole blood data were 136 L/h/m(2), 7.23 L/m(2), and 12.5 L/h/m(2). These results support using body surface area for calculating doses of amifostine in children. Similar to data in adults, amifostine and WR1065 are rapidly cleared from plasma and whole blood in children.