Abstract 4651: Characterization of the clinical pharmacokinetics of actinomycin D and the influence of pharmacogenetic variation in children with cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Actinomycin D (Act D) is an anti-tumor antibiotic commonly used in the treatment of cancer in children and adults. As part of a multimodal approach, Act D is a key component in the treatment of Wilms tumor, where cure rates as high as 90% have been achieved, Ewing sarcoma and rhabdomyosarcoma. However, although treatment with Act D is often successful, one of the main challenges associated with Act D therapy is treatment-related severe hepatic toxicity, which occurs in up to 15% of cases. Act D has been used clinically for over 50 years, however, only limited information is known about its pharmacokinetics, with only one substantive pediatric patient population studied. In addition, in contrast to many other established anticancer drugs, no studies have currently been performed to investigate the impact of pharmacogenetic variation on the pharmacokinetics of Act D in cancer patients. An increased knowledge of the clinical pharmacology of Act D may allow the development of more rational dosing regimens in children.The current study was therefore carried out to explore the influence of pharmacogenetics alongside a more definitive characterization of the pharmacokinetics of Act D in children with cancer. Act D (0.4 - 1.6 mg/m2) was administered to 117 patients ≤21 years recruited over an 8 year period, with samples for pharmacokinetic analysis collected over 24h. A total of 650 valid plasma samples were used to characterize a population pharmacokinetic model. Polymorphisms in ABCB1 were analyzed in 140 patients. A 3-compartment model provided a good fit to the data. Median values for Act D clearance and volume of distribution (V1) obtained from the model were 5.3L/h and 1.9L (13.9 L/h/70kg and 7.5 L/70kg), respectively. There was substantial inter-subject variation in all pharmacokinetic parameters (coefficients of variation 53-81%). Body size was a major determinant of Act D clearance, such that dose capping at 2mg in larger children at a protocol dose of 1.5mg/m2 resulted in significantly lower AUC values (mean AUC values: 9.3 versus 12.8 mg/L.min; P<0.0001). No significant relationships were found between ABCB1 genetic variants and Act D pharmacokinetic parameters, nor between CL, V1 or dose and incidence of grade 3 or 4 toxicity. We have defined the pharmacokinetics of Act D in a pediatric patient population, providing robust estimates of key pharmacokinetic parameters. In addition, pharmacokinetic data bring into question the clinical validity of dose capping at 2mg in larger patients. Pharmacogenetic variation in candidate drug transporter genes identified from preclinical studies does not significantly impact on Act D exposure in a clinical setting. Citation Format: Gareth J. Veal, Christopher R. Hill, Michael Cole, Julie Errington, Ghada Malik, Alan V. Boddy. Characterization of the clinical pharmacokinetics of actinomycin D and the influence of pharmacogenetic variation in children with cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4651. doi:10.1158/1538-7445.AM2014-4651