Benefits of pharmacological knowledge in the design and monitoring of cancer chemotherapy

Prescribing chemotherapy is a difficult task, because of drug resistance, which prevents all tumors to respond to a given protocol and because of drug toxicity, which is generally unavoidable but which must be limited to acceptable levels. The therapeutic window of anticancer drugs is very narrow and clinicians have to try to optimize the individual doses and schedules of the drugs to be administered. They can rely upon simple anthropometric features, such as body weight or surface area; they can also take into account the physiological status of the patient: age, liver and kidney function, genetic characteristics of drug metabolism, etc. The best way for dose adaptation lies in the establishment of pharmacokinetic/pharmacodynamic relationships, i.e., between the behavior of a drug in the body and its efficacy and toxicity. When it is established that the optimal effect of a drug is related to a given parameter, such as the area under the curve plotting plasma concentration vs. time (AUC), it becomes possible to administer the drug with the dose allowing to obtain the target parameter value. Individual dose adaptation can be achieved thanks to the study of the pharmacokinetics of a test dose preceding that of the therapeutic dose, or by the measure of drug plasma levels, either at steady state during a protracted infusion, or from cycle to cycle during repetitive protocols. Population analysis now allows the adaptation of anticancer drug dosing from a minimum knowledge of individual pharmacokinetic features, together with other characteristics of the patients such as age, gender or physiological functions.