Dose reduction of chemotherapeutic agents after weight loss

The aim of dose reduction of chemotherapeutic agents following weight loss is to avoid excessive toxicity while maintaining an equivalent therapeutic effect. Several methods of calculating this dose reduction are currently in use, including dose reduction in proportion to the reduction in body surface area (BSA) or the amount of weight lost and no dose reduction unless significant toxicity occurs. Each of these methods results in the administration of a different dose and therefore different drug exposure, as measured by the area under the time versus concentration curve (AUC). We have used pharmacokinetic modeling software and normative data on the pharmacokinetics of high-dose methotrexate to determine the change in AUC resulting from dose reduction by each of the methods cited for patients with weight loss. Dose reduction in proportion to the reduction in weight results in the same AUC and therefore equivalent drug exposure as before weight loss. In contrast, the more common practice of dose reduction in proportion to the decrease in BSA (as determined by recalculating BSA) results in a higher AUC than before weight loss. This results in increased drug exposure and potentially increased toxicity, which may be avoided if dose reduction is carried out in proportion to the decrease in weight rather than in BSA. The same principles are applicable to other drugs, particularly those associated with dose-dependent toxicity.