Introduction
Childhood leukemias are among the most drug-responsive of human malignancies. More than 70% of children with acute lymphoblastic leukemia (ALL) can now be cured, largely by systemic chemotherapy. Because of their drug responsiveness, childhood leukemias are a good model for evaluating the pharmacodynamics of anticancer drugs.
Pharmacokinetics is the study of the absorption, distribution, metabolism, and excretion of drugs. Pharmacodynamics describes the relationship between pharmacokinetics and pharmacologic effect, either adverse or desired. Substantial interindividual variability exists in the pharmacokinetics and in the pharmacodynamics of many antileukemic agents in children, and these data will not be reviewed herein. Pharmacogenetics is the study of the inherited basis for interindividual differences in response to medications. Thus, individualizing therapy on the basis of germline genetic status may be one means of minimizing interindividual variability in response to antileukemic agents.
Interpatient variability characterizes the disposition of many drugs. In the case of drugs with a wide therapeutic index (e.g. penicillins), such variability is unlikely to affect either clinical efficacy or toxicity. In the vast majority of patients, the drugs can be given in high enough doses to assure plasma concentrations that are very likely to produce the desired therapeutic response with little risk of toxicity. With antileukemic drugs, however, there is much less margin for error, due to their very narrow therapeutic index. Many investigations have established the relationship between administered dosage and plasma (or tissue) concentrations of drugs and metabolites, and in some cases between those concentrations or host genetic polymorphism and pharmacologic effect.