This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT There is a fundamental lack of knowledge regarding optimal dosing of anti-cancer agents for infants and young children, with resultant increased risk of morbidity, mortality, and inferior outcome. Two agents, actinomycin-D (Act-D) and vincristine (VCR) are of particular interest because little is known about their dose-exposure relationships. Act-D, a member of the antibiotic class of anti-neoplastic agents, has been used for the treatment of several childhood cancers since the 1960s. Despite its long-standing use in pediatric oncology, there is virtually no pharmacokinetic (PK) information from which safe and appropriate age-based pediatric dosing can be derived. The consequences of this lack of fundamental knowledge were evident as recently as 2002, when the Childrens Oncology Group (COG) suspended three active protocols for the treatment of children with rhabdomyosarcoma after four actinomycin associated deaths from hepatotoxicity. Act-D is an integral component of rhabdomyosarcoma and Wilms tumor therapy, and pediatric oncologists must continue to administer the drug despite the gap in knowledge. VCR, an anti-microtubule agent, is used in the treatment of many pediatric cancers. Neurotoxicity is commonly associated with VCR use, and is especially concerning in children under three years of age. In this study, we will perform a limited sampling PK study in children being treated with Act-D and VCR, using a validated liquid chromatography/tandem mass spectroscopy (LC/MS/MS) assay capable of simultaneously quantifying Act-D and VCR in plasma to a lower limit of quantification of 0.05 ng/mL. Using both standard statistical analyses and a mixed-effects modeling approach, we will describe Act-D and VCR PK, and identify factors which may be determinants of Act-D and VCR disposition. The resulting PK model will be used to derive individual patient exposure metrics and describe the correlation of drug exposure to toxicity. This is an attempt to develop a universal dosing scheme for Act-D and VCR that maximizes therapeutic outcome and minimizes therapeutic risk. We will additionally investigate pharmacogenetic correlations of drug metabolizing enzymes and drug transporters and determine the correlation between genetic variation in drug metabolizing enzymes and drug transporters and observed drug PK and pharmacodynamics (PD) in children. The results of these studies will enhance our understanding of the variability in drug disposition, toxicity, and pharmacologic effect.
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