Prediction of Human Clearance of Therapeutic Proteins: Simple Allometric Scaling Method Revisited

In this report, the utility of a commonly used interspecies scaling method to predict the systemic clearance (CL) of therapeutic proteins in humans was evaluated. Based on analysis of a pharmacokinetic data set of 34 therapeutic proteins, including 12 monoclonal antibodies (mAbs) and Pc fusion proteins, human CL can generally be predicted reasonably well with simple allometric scaling and a fixed exponent of 0.8:similar to 95% of the cases predicted values within 2-fold of the observed values when using CL data from multiple species, or similar to 90% simply using CL from monkeys. Specific to mAbs/Fc fusion proteins, scaling from monkey CL using a fixed exponent of 0.8 gave an excellent prediction; all predicted CL values were within 2-fold of the corresponding observed values. Compared with the simple allometric scaling method that uses a fitted exponent from CL data of >= 3 preclinical species, the fixed exponent approach with 1-2 preclinical species is simple, resource-saving and minimizes systematic bias. Together with its overall satisfactory prediction accuracy, especially in the absence of non-linear pharmacokinetics and species-specific clearance mechanisms, this fixed exponent method affords a viable alternative to other published allometric methods, including the Rule of Exponents (ROE). Copyright (C) 2010 John Wiley & Sons, Ltd.