Pharmacokinetics of dactinomycin in a pediatric patient population: a United Kingdom Children's Cancer Study Group Study.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Gareth J Veal, Michael Cole, Julie Errington, Annie Parry, Juliet Hale, Andrew D J Pearson, Karen Howe, Julia C Chisholm, Carol Beane, Bernadette Brennan, Fiona Waters, Adam Glaser, Sue Hemsworth, Heather McDowell, Yvonne Wright, Kathy Pritchard-Jones, Ross Pinkerton, Gail Jenner, James Nicholson, Ann M Elsworth, Alan V Boddy, Kingdom Children's Cancer Study Group Pharmacology Working Group
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 16 Pg. 5893-9 (Aug 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16115931 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Antineoplastic Agents, Alkylating
• Dactinomycin
• Ifosfamide

Topics

• Adolescent
• Adult
• Analysis of Variance
• Antibiotics, Antineoplastic (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents, Alkylating (therapeutic use)
• Area Under Curve
• Child
• Child, Preschool
• Chromatography, Liquid
• Dactinomycin (administration & dosage, blood, pharmacokinetics)
• Dose-Response Relationship, Drug
• Female
• Fever (chemically induced)
• Humans
• Ifosfamide (therapeutic use)
• Infections (chemically induced)
• Infusions, Intravenous
• Male
• Mass Spectrometry
• Metabolic Clearance Rate
• Neoplasms (drug therapy, metabolism)
• Time Factors