title: Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited.
abstract: 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 Fc fusion proteins, human CL can generally be predicted reasonably well with simple allometric scaling and a fixed exponent of 0.8: approximately 95% of the cases predicted values within 2-fold of the observed values when using CL data from multiple species, or approximately 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 > or =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).
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Merck Sharp & Dohme Corp., West Point, PA 19486, USA. weirong_wang@merck.com
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.forename: Thomayant
authors.initials: T
authors.lastname: Prueksaritanont
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D000882:Haplorhini; D006801:Humans; D008954:Models, Biological; D011506:Proteins / Q000493:pharmacokinetics*; D013045:Species Specificity
chemical_list: D000911:Antibodies, Monoclonal; D011506:Proteins