Pharmacokinetically guided administration of chemotherapeutic agents.

Abstract

The current practice for the dose calculation of most anticancer agents is based on body surface area in m2, although lower interpatient variation in pharmacokinetic parameters has been reported with pharmacokinetically guided administration. As chemotherapeutic agents have a narrow therapeutic window, pharmacokinetically guided administration may lead to less toxicity and higher efficacy than administration on the basis of body surface area. Pharmacokinetically guided administration, using parameters such as area under the plasma concentration-time curve (AUC), steady-state plasma drug concentration and drug exposure time above a certain plasma concentration, has been studied for many antineoplastic agents. Assessment of pharmacokinetic profiles allows the characterisation of relationships between pharmacokinetic parameters and efficacy and toxicity. AUC appears to be more closely correlated with pharmacodynamics than does the dose per unit of body surface area. In particular, the AUC-guided administration of carboplatin has been extensively studied, based on the close relationship between the renal clearance of the drug and glomerular filtration rate. Several formulae and limited sampling models have been derived to predict the AUC of carboplatin. The relationship between AUC and pharmacodynamics has also been studied for other anticancer agents, for example fluorouracil, topotecan, etoposide, cisplatin and busulfan, but all less extensively than for carboplatin. The pharmacokinetically guided administration of these agents needs to be investigated further before the use of alternative administration formulae can become standard clinical practice. Prospective studies of pharmacokinetically guided versus surface area-based administration should be performed to validate pharmacokinetic-pharmacodynamic relationships and to facilitate optimal dosage of anticancer agents in the clinic.