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The Importance of Pharmacokinetic Limited Sampling Models for Childhood Cancer Drug Development

Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee [J. C. P., L. C. I., C. F. S.], and The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania [P. C. A.]

ABSTRACT

Since the development of effective chemotherapy for children with cancer, it has been recognized that the response of children to apparently identical therapy, both in terms of efficacy and toxicity, can vary widely. Our understanding of the interindividual differences in drug metabolism and disposition as significant determinants of drug response continues to evolve. An increasing area of clinical investigation is focused on studies to gain a better understanding of the variability in critical drug metabolic and elimination pathways and how this variability translates into varied pharmacological effects. Analyzing how drug metabolism and elimination are affected by patient characteristics such as age, sex, race, organ function, drug interactions, and, perhaps most importantly, genetic polymorphisms, is now a routine component of drug development studies. Recent advances in analytical methodologies, computer hardware, and pharmacokinetic software have improved our ability to conduct studies of the disposition of anticancer drugs in larger, more representative pediatric cancer populations. Along with advances in pharmacogenetics, the advances made in the conduct of pharmacokinetic studies in children with cancer have enabled establishment of sophisticated phenotype-genotype correlations, which may ultimately improve care. However, unique challenges and limitations remain that complicate the performance of pharmacokinetic studies in the child with cancer. This review addresses the need to perform pharmacokinetic studies throughout the drug development process in pediatric oncology patients, methods used to develop and validate limited sampling models, and selected examples of limited sampling models used in pharmacokinetic studies in children with cancer.

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