Cancer Therapy: Clinical Pharmacokinetics of Dactinomycin in a Pediatric Patient Population: a United Kingdom Children’s Cancer Study Group Study Gareth J. Veal,1 Michael Cole,1 Julie Errington,1 Annie Parry,2 Juliet Hale,2 Andrew D.J. Pearson,2 Karen Howe,3 Julia C. Chisholm,3 Carol Beane,4 Bernadette Brennan,4 Fiona Waters,5 Adam Glaser,5 Sue Hemsworth,6 Heather McDowell,6 Yvonne Wright,7 Kathy Pritchard-Jones,7 Ross Pinkerton,7 Gail Jenner,8 James Nicholson,8 Ann M. Elsworth,9 Alan V. Boddy,1 and UKCCSG Pharmacology Working Group 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 pharmaco- kinetics in children. Experimental Design: Dactinomycin was administered to 31patients by bolus i.v. infusion, at doses of 0.70 to1.50 mg/m2. Plasma concentrations were determined by liquid chromatography- mass spectrometry up to 24 hours after drug administration and National Cancer Institute Com- monToxicity Criteria was assessed. Results: Pharmacokinetic data analysis suggested that a three-compartment model most accurately reflected dactinomycin pharmacokinetics. However, there was insufficient data avail- able to fully characterize this model. A median peak plasma concentration (Cmax)of25.1ng/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 =0.03andP = 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. Dactinomycin(actinomycinD;Fig.1)isanantitumor both adults and children. The drug has been a key component antibiotic used routinely to treat certain forms of cancer in in the successful treatment of Wilms tumor patients over the past 30 years, with >80% of patients treated now being cured of the disease (1–3). However, despite its long history of clinical Authors’ Affiliations: 1Northern Institute for Cancer Research; 2School of Clinical use, limited knowledge exists concerning the relationship Medical Sciences (Child Health), University of Newcastle upon Tyne, Newcastle between dactinomycin dosing and pharmacokinetics. uponTyne; 3Department of Haematology/Oncology, Great Ormond Street Hospital, London; 4Department of Paediatric Oncology, Manchester Children’s Hospital, Dactinomycin is most commonly administered to pediatric Manchester; 5Paediatric Oncology Unit, St. James’s Hospital, Leeds; 6Royal patients as a single bolus i.v. injection. The dose is based on a Liverpool Children’s Hospital, Alder Hey, Liverpool; 7Royal Marsden Hospital, child’s calculated body surface area, with a 3- to 9-week interval 8 Surrey; Department of Paediatrics, Addenbrooke’s Hospital, Cambridge; and between courses depending on the tumor type and disease stage. 9UKCCSG, University of Leicester, Leicester, United Kingdom Received 12/13/04; revised 5/16/05; accepted 5/27/05. The dosing regimen for infants is modified, with patients <1 year Grant support: Supported in part by Cancer Research U.K. G.J. Veal was a old at diagnosis, or weighing <10 kg, frequently receiving a recipient of an AACR-GlaxoSmithKline Outstanding Clinical Scholar award. reduced dose based on body weight (4). For example, a standard The costs of publication of this article were defrayed in part by the payment of page dactinomycin dose of 1.5 mg/m2 is commonly adjusted to charges. This article must therefore be hereby marked advertisement in accordance 25 Ag/kg from birth to 6 months of age and to 1.0 mg/m2 from with 18 U.S.C. Section 1734 solely to indicate this fact. Note: This work was presented in part at the 95th Annual AACR meeting, March 27 6 months to 1 year or <10 kg body weight. This is further to 31, Orlando, FL. complicated in some clinical protocols by the fact that once a Requests for reprints: Alan V. Boddy, Northern Institute for Cancer Research, child reaches 10 kg, doses are recalculated as dose/m2 but kept at Paul O’Gorman Building, Medical School, Framlington Place, University of 50% (0.75 mg/m2) until their first birthday. Alternatively, a Newcastle uponTyne, Newcastle uponTyne NE2 4HH, United Kingdom. Phone: A 44-191-246-4412;Fax: 44-191-246-4301;E-mail: [email protected]. dose of 50 g/kg may be prescribed for children aged 1 to 3 2 F 2005 American Association for Cancer Research. years, with the conventional dose of 1.5 mg/m only being doi: 10.1158/1078-0432.CCR-04-2546 used for children >3 years of age (5). www.aacrjournals.org 5893 Clin Cancer Res 2005;11(16) August 15, 2005 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2005 American Association for Cancer Research. Cancer Therapy: Clinical Patients and Methods Patient eligibility and treatment. The study protocol was approved by the U.K. Trent Multicentre Ethics Committee and participating centers obtained local ethical approval; written informed consent was required, either from patients or parents as appropriate, for all patients entered onto the study. Patients 21 years or younger, receiving dactinomycin chemotherapy as part of their standard clinical treatment, were eligible (Table 1). All patients were required to have central venous access, in the form of single or double lumen central venous catheters or Port-a-Caths, in order to participate in this pharmacokinetic study. Dactinomycin (0.70-1.50 mg/m2) was administered by bolus i.v. infusion as part of the standard chemotherapy regimen that each patient was currently receiving. Toxicity was assessed by the National Cancer Institute Common Toxicity Criteria (CTC), version 2.0, Fig. 1. Chemical structure of dactinomycin (MW1,255). following dactinomycin treatment. Blood sampling and analysis. Blood samples for measurement of Dosage regimens for the treatment of patients with Wilms dactinomycin concentration were obtained from a central line prior to tumor in the U.K. have been revised on more than one occasion administration and at 15 and 30 minutes, and 1, 2, 4, 6, and 24 hours due to concerns regarding potential underdosing or a possible post-administration. Actual sampling times were recorded for all patients studied and were as follows (median value and range given): link between toxicity from venoocclusive disease of the liver 15 minutes, 17 (15-25); 30 minutes, 32 (26-50); 60 minutes, 60 and dactinomycin dosing. Similar amendments to dosing were (57-68); 120 minutes, 122 (112-132); 240 minutes, 241 (215-297); required during a Children’s Oncology Group study for the 360 minutes, 360 (330-385); 1,440 minutes, 1,440 (1,295-1,531). All treatment of rhabdomyosarcoma (5). Venoocclusive disease, a eight samples were obtained in a total of seven children, with between severe hepatic toxicity with a reported incidence of 2% to two and seven samples obtained from the remaining patients; most 13.5% across different clinical studies (6–8), is the main frequently with the omission of the 24 hours post-administration drawback to the clinical use of dactinomycin. However, despite sample. The actual number of samples obtained at each of the specified the many changes to the dosing of dactinomycin, optimum time points are given in Table 2. Samples were obtained from 17 patients dosage regimens for the treatment of infants and young with double lumen central venous catheters, 9 patients with single children remain unclear. As dactinomycin is metabolized in lumen lines, and 5 patients with Port-a-Cath access. All lines were the liver, with both the liver and kidneys involved in drug flushed thoroughly following administration of dactinomycin and prior to the withdrawal of samples for pharmacokinetic analysis and separate excretion, development of renal and hepatic function in young drug infusion and sampling sites were used whenever possible. Blood children may be an important factor in influencing its clinical samples (2 mL) were collected in heparinized tubes and centrifuged at pharmacology. This could potentially lead to significant 1,200 Â g for 10 minutes at 4jC. Plasma was separated and frozen at variations in drug pharmacokinetics between infants and older À20jC prior to analysis using a validated liquid chromatography-mass children. spectrometry assay, with a limit of quantitation of 1.0 ng/mL (13). As the dose intensity of dactinomycin treatment has been clearly defined as a significant risk factor for the development of hepatotoxicity in Wilms tumor, it would seem logical to carry out pharmacokinetic studies in these patients. This would allow Ta b l e 1. Patient characteristics potential correlations to be investigated between the extent of interpatient variation in exposure to dactinomycin and clinical Characteristic No. of patients (%) response and toxicity. However, to date, there is a paucity of Age (y) information regarding the clinical pharmacology of dactino- <511(36) mycin, with no pharmacokinetic studies having been carried 5-9 8 (26) out in pediatric patients, and a very limited number of studies 10-14 6 (19) in adults. Indeed, the only publications in this area are those 15 -20 6 (19) focusing on the analytical methods developed, with data from Sex one or two patients to show a clinical application (9–12). No Male 18 (58) dactinomycin pharmacokinetic study has been published using Female 13(42) these methods, possibly due to concerns over a lack of Diagnosis specificity for the parent drug, or due to the labor-intensive Wilms tumor 9 (29) nature of the methods, making the analysis of large numbers of Ewing sarcoma 7 (23) clinical samples unrealistic.