BSA-adjusted dose? An old method to fight old bias
Sylvain Fouliard and Marylore Chenel
Department of Clinical Pharmacokinetics, Institut de Recherches Internationales Servier, France
Objectives: By taking into account inter-individual variability in drug distribution, metabolism and/or elimination, individual dose adjustment lowers inter-individual variability in exposure. When given at a fixed dose, drugs with a wide therapeutic range, between effective dose and maximum tolerated dose (MTD), lead to a variable, but safe individual exposure. On the other hand in oncology, where therapeutic drug dose is closer to MTD, the therapeutic range is narrower. In this context, dose adjustment may help in reducing exposure variability, and better control the optimal dose in terms of efficacy and safety. Body surface area (BSA) is frequently used for dose-adjustment, as it has been shown to correlate with total blood volume, cardiac output and renal function [1]. Still, BSA-adjusted dose relies on a strong assumption on the linear relationship between exposure (i.e. drug clearance) and BSA. A different relationship may lead at best to unnecessary constraints on drug prescription and at worst to an increase of exposure variability across patients. Our work aims at evaluating the link between drug clearance and BSA, in order to choose the best dosing strategy in drug SX development.
Methods: PK data from two studies (49 patients, drug SX given intravenously and orally) was used to build a population model M0. Individual empirical Bayesian estimates (EBEs) of plasma clearance (CLi) were then computed. Model M1 was built, where clearance was supposed to be proportional to BSA, and was used to define a second set (CLi') of EBEs. Naïve predictor prediction error and model prediction error were computed according to [2], using respectively (CLi) and (CLi'). The two predictors were then compared by computing median prediction error as a measure of bias and median unsigned prediction as a measure of precision. Graphical representation developed in [2] was used to allow a visual evaluation of comparative predictor performance. Models were also compared in terms of objective function values (OFV, = -2 log-likelihood). NONMEM VI FOCE-I, was used for model building.
Results: Models M1 and M0 gave similar population and individual estimates of parameters. A difference of 8 in OFV between M1 and M0 showed a significant effect of BSA on clearance. M0 and M1 gave respectively a prediction error on clearance of 38 % and 34 %.
Conclusion: In the context of early drug development in oncology, this work evaluated the relevance of dose adjustment based on BSA, in a quantitative and visually intelligible way. The reduction of variability induced by BSA-adjusted dose was found to be too small to justify dose adjustment in further development.
References:
[1] Pinkel D, The use of body surface area as a criterion of drug dosage in cancer chemotherapy. Cancer Res 1958; 18: 853-6.
[2] Bruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Sheiner LB. A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J. Pharmacokinet Biopharm. 1996 Apr; 24(2):153-72.