title: Pharmacokinetics of dactinomycin in a pediatric patient population: a United Kingdom Children's Cancer Study Group Study.
abstract: OBJECTIVE
  Dactinomycin (actinomycin D) is an antitumor antibiotic used routinely to treat certain pediatric and adult cancers. Despite concerns over the incidence of toxicity, little is known about the pharmacology of dactinomycin. A study was done to investigate dactinomycin pharmacokinetics in children.
  
  
  METHODS
  Dactinomycin was administered to 31 patients by bolus i.v. infusion, at doses of 0.70 to 1.50 mg/m2. Plasma concentrations were determined by liquid chromatography-mass spectrometry up to 24 hours after drug administration and National Cancer Institute Common Toxicity Criteria was assessed.
  
  
  RESULTS
  Pharmacokinetic data analysis suggested that a three-compartment model most accurately reflected dactinomycin pharmacokinetics. However, there was insufficient data available to fully characterize this model. A median peak plasma concentration (Cmax) of 25.1 ng/mL (range, 3.2-99.2 ng/mL) was observed at 15 minutes after administration. The median exposure (AUC0-6), determined in 16 patients with sampling to 6 hours, was 2.67 mg/L.min (range, 1.12-4.90 mg/L.min). After adjusting for body size, AUC0-6 and Cmax were positively related to dose (P = 0.03 and P = 0.04, respectively). Patients who experienced any level of Common Toxicity Criteria grade had a 1.46-fold higher AUC0-6, 95% confidence interval (1.02-2.09). AUC0-6 was higher in patients <40 kg, possibly indicating a greater toxicity risk.
  
  
  CONCLUSIONS
  Data presented suggest that dosing of dactinomycin based on surface area is not optimal, either in younger patients in whom the risk of toxicity is greater, or in older patients where doses are capped.
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle upon Tyne, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Veal
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.forename: Julie
authors.initials: J
authors.lastname: Errington
authors.forename: Annie
authors.initials: A
authors.lastname: Parry
authors.forename: Juliet
authors.initials: J
authors.lastname: Hale
authors.forename: Andrew D J
authors.initials: AD
authors.lastname: Pearson
authors.forename: Karen
authors.initials: K
authors.lastname: Howe
authors.forename: Julia C
authors.initials: JC
authors.lastname: Chisholm
authors.forename: Carol
authors.initials: C
authors.lastname: Beane
authors.forename: Bernadette
authors.initials: B
authors.lastname: Brennan
authors.forename: Fiona
authors.initials: F
authors.lastname: Waters
authors.forename: Adam
authors.initials: A
authors.lastname: Glaser
authors.forename: Sue
authors.initials: S
authors.lastname: Hemsworth
authors.forename: Heather
authors.initials: H
authors.lastname: McDowell
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wright
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: Ross
authors.initials: R
authors.lastname: Pinkerton
authors.forename: Gail
authors.initials: G
authors.lastname: Jenner
authors.forename: James
authors.initials: J
authors.lastname: Nicholson
authors.forename: Ann M
authors.initials: AM
authors.lastname: Elsworth
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D003609:Dactinomycin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007069:Ifosfamide / Q000627:therapeutic use; D007239:Infections / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D003609:Dactinomycin; D007069:Ifosfamide