PHARMACOKINETICS AND PHARMACODYNAMICS OF ANTILEUKEMIC AGENTS IN CHILDREN

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The long-term objectives of this project are to characterize the pharmacokinetics (absorption, distribution, metabolism and elimination) of antileukemic drugs in children; to determine patient and/or disease characteristics influencing the disposition of these agents in children; to assess the relation of drug disposition to drug effects (i.e., pharmacodynamics); and to ultimately integrate these data to develop models for establishing optimal dosages and schedules of these drugs for the treatment of childhood leukemia. The pharmacokinetics of anticancer drugs are often significantly different in children when compared to adults, precluding the use of adult pharmacokinetic data to establish optimal dosages for children. Studies here are designed to address three major gaps in our existing knowledge of the pharmacokinetics and pharmacodynamics of antileukemic drugs in children. The first aim addresses whether drug dosage and interpatient variability in drug disposition have a significant effect on the concentration of drug achieved in acute lymphocytic leukemia (ALL) blast cells in vivo. The initial studies will be conducted in newly diagnosed ALL patients randomized to single agent therapy with either high-dose methotrexate (MTX) of low-dose MTX. MTX and its active polyglutamates and folylpolyglutamate synthetase (FPGS) activity will be measured in ALL blasts in vivo, along with biochemical measures of MTX's pharmacologic effects (e.g., PRPP, folates). These will be the first human studies to assess blast cell pharmacokinetics/dynamics in vivo, and will help to define optimal dosages of MTX. The second aim utilizes a novel in vitro method of assessing ALL blast cell sensitivity to each antileukemic agent; it then examines the ratio of systemic exposure to each drug relative to blast cell sensitivity, with the goal of identifying patients at highest risk of relapse. Such data could provide a method for identifying those patients who should be treated with more intensive chemotherapy. the third aim investigates a novel design ("MTSE") for conducting pediatric Phase I trials of new antileukemic agents, in which systemic exposure is escalated instead of drug dosage. The MTSE study has the potential advantage of controlling interpatient pharmacokinetic variability and thereby more precisely defining the maximum level of treatment intensity for future Phase II pediatric trials. Collectively, these studies will contribute substantially to our goal of designing ALL chemotherapy that has maximal efficacy and minimal toxicity.