Pharmacokinetics of dactinomycin in a pediatric patient population: a United Kingdom Children's Cancer Study Group Study.
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.
Veal
Gareth J
GJ
Northern Institute for Cancer Research, University of Newcastle upon Tyne, UK.
Cole
Michael
M
Errington
Julie
J
Parry
Annie
A
Hale
Juliet
J
Pearson
Andrew D J
AD
Howe
Karen
K
Chisholm
Julia C
JC
Beane
Carol
C
Brennan
Bernadette
B
Waters
Fiona
F
Glaser
Adam
A
Hemsworth
Sue
S
McDowell
Heather
H
Wright
Yvonne
Y
Pritchard-Jones
Kathy
K
Pinkerton
Ross
R
Jenner
Gail
G
Nicholson
James
J
Elsworth
Ann M
AM
Boddy
Alan V
AV
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
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D003609:Dactinomycin; D007069:Ifosfamide