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Pharmacokinetics of Dactinomycin in a Pediatric Patient Population: a United Kingdom Children's Cancer Study Group Study

Authors' Affiliations: ¹ Northern Institute for Cancer Research; ² School of Clinical Medical Sciences (Child Health), University of Newcastle upon Tyne, Newcastle upon Tyne; ³ Department of Haematology/Oncology, Great Ormond Street Hospital, London; ⁴ Department of Paediatric Oncology, Manchester Children's Hospital, Manchester; ⁵ Paediatric Oncology Unit, St. James's Hospital, Leeds; ⁶ Royal Liverpool Children's Hospital, Alder Hey, Liverpool; ⁷ Royal Marsden Hospital, Surrey; ⁸ Department of Paediatrics, Addenbrooke's Hospital, Cambridge; and ⁹ UKCCSG, University of Leicester, Leicester, United Kingdom

Requests for reprints: Alan V. Boddy, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Framlington Place, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom. Phone: 44-191-246-4412; Fax: 44-191-246-4301; E-mail: alan.boddy{at}ncl.ac.uk.

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 (C_max) of 25.1 ng/mL (range, 3.2-99.2 ng/mL) was observed at 15 minutes after administration. The median exposure (AUC_0-6), 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, AUC_0-6 and C_max 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 AUC_0-6, 95% confidence interval (1.02-2.09). AUC_0-6 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.

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