title: Towards a platform PBPK model to characterize the plasma and tissue disposition of monoclonal antibodies in preclinical species and human.
abstract: The objectives of the following investigation were (1) development of a physiologically based pharmacokinetic (PBPK) model capable of characterizing the plasma and tissue pharmacokinetics (PK) of nonspecific or antigen specific monoclonal antibodies (mAbs) in wild type, FcRn knockout, tumor bearing and non tumor bearing mice and (2) evaluation of the scale up potential of the model by characterizing the mouse, rat, monkey and human plasma PK of mAbs, simultaneously. A PBPK model containing 15 tissues, a carcass and a tumor compartment was developed by modifying/augmenting previously published PBPK models. Each tissue compartment was subdivided into plasma, blood cell, endothelial, interstitial and cellular sub-compartments. Each tissue was connected through blood and lymph flow to the systemic circulation. Lymph flow was set to a value 500 times lower than plasma flow and vascular reflection coefficients for each tissue were adjusted according to their vascular pore size. In each tissue endothelial space, mAb entered via pinocytosis and the interaction of FcRn with mAb was described by on and off rates. FcRn bound mAb was recycled and unbound mAb was eliminated by a first order process (K(deg)). The PBPK model was simultaneously fit to the following datasets to estimate four system parameters: (1) plasma and tissue PK of nonspecific mAb in wild type mouse with or without simultaneous intravenous immunoglobulin (IVIG) administration, (2) plasma and tissue PK of nonspecific mAb in FcRn knockout mouse, (3) plasma and tissue PK of nonspecific mAb in tumor bearing mouse, (4) plasma and tissue PK of tumor antigen specific mAb in tumor bearing mouse, and (5) plasma PK of mAb in rat, monkey and human. The model was able to characterize all the datasets reasonably well with a common set of parameters. The estimated value of the four system parameters i.e. FcRn concentration (FcRn), rate of pinocytosis per unit endosomal space (CL(up)), K(deg) and the proportionality constant (C_LNLF) between the rate at which antibody transfers from the lymph node compartment to the blood compartment and the plasma flow of the given species, were found to be 4.98E-05 M (CV% = 11.1), 3.66E-02 l/h/l (%CV = 3.48), 42.9 1/h (%CV = 15.7) and 9.1 (CV% > 50). Thus, a platform PBPK model has been developed that can not only simultaneously characterize mAb disposition data obtained from various previously published mouse PBPK models but is also capable of characterizing mAb disposition in various preclinical species and human.
authors.affiliation: Translational Research Group, Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development Groton Labs, MS 8220-4573, Eastern Point Road, Groton, CT 06340, USA. Dhavalkumar.K.Shah@pfizer.com
authors.forename: Dhaval K
authors.initials: DK
authors.lastname: Shah
authors.forename: Alison M
authors.initials: AM
authors.lastname: Betts
mesh_terms: D000068879:Adalimumab; D000465:Algorithms; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood* / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000493:pharmacokinetics; D000951:Antigens, Neoplasm / Q000276:immunology; D019540:Area Under Curve; D001769:Blood / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D011992:Endosomes / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D000882:Haplorhini; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D008196:Lymph / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D010873:Pinocytosis / Q000502:physiology; D051381:Rats; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; D016756:Immunoglobulins, Intravenous; C121421:MOPC21 monoclonal antibody; D011961:Receptors, Fc; D000068879:Adalimumab; C100688:Fc receptor, neonatal