Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative.

Abstract

PURPOSE: To review the current dose-calculation practice and propose a non-body-surface area (BSA)-based dose-calculation method. METHODS: Data that supported the introduction of BSA-based dose calculation in the late 1950s were reviewed. Data on 18 drugs that correlated pharmacokinetic (PK) variables for cytotoxic drugs with BSA were examined. Other methods of dose calculation, such as therapeutic drug monitoring (TDM) and adaptive control, were also examined. RESULTS: The BSA-based method of dose calculation was adopted without adequate investigation of its accuracy. BSA fails to standardize the marked interpatient variation in PK for most cytotoxic drugs. A definite correlation was found between PK variables and BSA for only one drug (docetaxel). PK parameters correlate with toxicity, as well as response in some tumors, but do not completely explain the variation in drug effect between individuals. The complexities of TDM may make its universal use impractical. A non-BSA-based dose calculation method is proposed that defines three mandatory steps: prime dose, modified dose, and toxicity-adjusted dose (PMT dosing). Prime dose is the fixed dose of a drug used alone or in combination and is derived from the reanalysis of phase I/II studies and from clinical practice. Modified dose is an adjustment of the prime dose before administration, based on dose-adjustment guidelines that predict the drug-handling ability of an individual. Population pharmacodynamic studies may be used for the development of these guidelines. Subsequent doses are adjusted in each patient according to a target toxicity, such as nadir neutrophil count or other objective toxicity, that serves as a surrogate marker for potential antitumor effect (toxicity-adjusted dose). Patients who are predicted to have very abnormal drug handling should be excluded from such a dosing scheme and TDM may be more suitable. CONCLUSION: The routine use of BSA for dose calculation should be reevaluated. Other methods of dose calculation should be investigated. TDM may be impractical in all patients and remains unvalidated. PMT dosing ensures that the condition of each individual is considered, to predict drug effects better. Clinical dose-calculation systems such as PMT dosing should be evaluated prospectively.