title: Clinical pharmacokinetics of amifostine and WR1065 in pediatric patients with medulloblastoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Sciences, University of Tennessee, TN, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: McKibbin
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.forename: M Fatih
authors.initials: MF
authors.lastname: Okcu
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000328:Adult; D004999:Amifostine / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002528:Cerebellar Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D008624:Mercaptoethylamines / Q000493:pharmacokinetics; D011355:Prodrugs / Q000378:metabolism*
chemical_list: D008624:Mercaptoethylamines; D011355:Prodrugs; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine