title: Allometric Scaling of Therapeutic Monoclonal Antibodies Using Antigen Concentration as a Correction Factor: Application to the Human Clearance Prediction.
abstract: Allometric scaling has been widely used for predictions of human pharmacokinetic (PK) parameters in the development of monoclonal antibody (mAb) drugs, and some correction factors have been proposed to improve the estimations. However, classic correction factors fail to offer a complete explanation of the additional differences among species besides the body weight and, thus, lack enough power to further improve the predictions. In this study, the antigen concentration was initially set as a new correction factor to predict the human clearance (CL) of mAbs. Bevacizumab was intravenously injected into 2 animal species and humans to obtain PK data to predict human CL from the animal data. Additionally, a new approach was also validated with data from 3 other mAbs which were collected through a literature review of published work. Accordingly, allometric scaling with a correction factor of the antigen concentration generated accurate estimations of the human CL of 4 mAbs, which were superior to the results obtained by other classic scaling methods. More importantly, the proposed method also achieved good predictions of individual human CL of bevacizumab. In conclusion, the potential of this method as a powerful tool for human PK estimation of mAbs in species translation has been demonstrated.
authors.affiliation: Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiang
authors.affiliation: Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China. Electronic address: chengzn@csu.edu.cn.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D000941:Antigens / Q000378:metabolism*; D000068258:Bevacizumab / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology*; D011817:Rabbits; D013045:Species Specificity; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; D000068258:Bevacizumab
keywords: clearance; clinical pharmacokinetics; preclinical pharmacokinetics; proteins; simulations