Role of Body Surface Area in Dosing of Investigational Anticancer Agents in Adults, 1991-2001

Abstract

The prescribed dose of anticancer agents is most commonly calculated using body surface area as the only independent variable, and it has been shown that this approach still results in large interpatient variability in drug exposure. Here, we retrospectively assessed the pharmacokinetics of 33 investigational agents tested in phase I trials from 1991 through 2001, as a function of body surface area in 1650 adult cancer patients. Twelve of the drugs were administered orally, 19 were administered intravenously, and two were administered by both routes. Body surface area-based dosing was statistically significantly associated with a reduction in interpatient variability in drug clearance for only five of the 33 agents: docosahexaenoic acid (DHA)-paclitaxel, 5-fluorouracil/eniluracil, paclitaxel, temozolomide, and troxacitabine. These results do not support the use of body surface area in dose calculations and suggest that alternate dosing strategies should be evaluated. We conclude that body surface area should not be used to determine starting doses of investigational agents in future phase I studies.

Patient Characteristics Compete with Dose as Predictors of Acute Treatment Toxicity in Early Phase Clinical Trials

“…This is consistent with the lack of correlation of pharmacokinetic parameters of most cytotoxic agents with body surface area or other measures of body size (12). The observation that the TI and the occurrence of DLT both correlate poorly with the method of dose calculation further indicts the reflexive use of body surface area-based dosing of new agents in early clinical trials.…”

Individualized Dosing with Axitinib: Rationale and Practical Guidance

“…However, it was known that multiple factors beyond patient size (including age, sex, renal function, hepatic function, concomitant medication, disease state and genetics) could have an impact on the actual concentration of a drug in an individual's bloodstream [4]. Consequently, there remains high variability between patients (interpatient variability) in systemic drug concentrations, even when normalized for weight/body surface area [5].…”

“…However, it was known that multiple factors beyond patient size (including age, sex, renal function, hepatic function, concomitant medication, disease state and genetics) could have an impact on the actual concentration of a drug in an individual's bloodstream [4]. Consequently, there remains high variability between patients (interpatient variability) in systemic drug concentrations, even when normalized for weight/body surface area [5].When molecular targeted agents were first introduced for use in metastatic renal cell carcinoma (mRCC), these drugs were recommended at a fixed dose, based on an assumption that the maximum tolerated fixed dose would result in the best efficacy and that this same high dose would be appropriate for all patients. However, most tyrosine kinase inhibitors (TKIs) demonstrate high interpatient variability in drug exposure (depending on oral bioavailability and first-pass liver metabolism of drugs); therefore, the subsequent therapeutic effect and toxicity for the same administered dose may vary [6].…”

Pharmacogenetics in the treatment of breast cancer

“…Currently, there is no consensus regarding how to dose people who are not at their ideal body weight, whether adjustments should be made based on age and toxicity, or lack of it, to the treatment, or whether BSA should be used to determine dose of chemotherapy and novel treatments. 38 Many women and their healthcare professionals will accept modest drugrelated toxicity for modest improvement in outcome. However, decisionmaking is especially difficult for women with very small tumors that are likely cured of their cancer by local modalities who may gain little benefit, Pharmacogenetics in breast cancer treatment V Stearns et al if any, from the addition of adjuvant chemotherapy.…”