title: Projecting human pharmacokinetics of monoclonal antibodies from nonclinical data: comparative evaluation of prediction approaches in early drug development.
abstract: Currently, more than 350 monoclonal antibodies (mAbs) and mAb derivatives are under development as therapeutics. The prediction of mAb pharmacokinetics (PK)/pharmacodynamics (PD) plays a key role in starting dose selection for first-in-human (FIH) studies. This article presents a brief overview of the biology and mechanisms of absorption, distribution, metabolism and excretion (ADME) for mAbs. In addition, a detailed review of mAb human PK/PD prediction from nonclinical data is provided, including allometry for mAbs with linear or nonlinear PK, species-invariant time method, physiologically based PK (PBPK) modeling and target-mediated drug disposition (TMDD) model, bioavailability projection and immunogenicity impact on PK prediction. Finally, from an industry perspective a decision tree of mAb human PK projection is proposed to facilitate drug development.
authors: Global DMPK, Takeda California, San Diego, CA, USA.|Tesaro, Inc., Waltham, MA, USA.
authors: Jing
authors: J
authors: Wang
authors: Genentech Research and Early Development, Genentech Inc., South San Francisco, CA, USA.|AbbVie Biotherapeutics, Redwood City, CA, USA.
authors: Suhasini
authors: S
authors: Iyer
authors: Genentech Research and Early Development, Genentech Inc., South San Francisco, CA, USA.
authors: Paul J
authors: PJ
authors: Fielder
authors: Genentech Research and Early Development, Genentech Inc., South San Francisco, CA, USA.|Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
authors: John D
authors: JD
authors: Davis
authors: Genentech Research and Early Development, Genentech Inc., South San Francisco, CA, USA.
authors: Rong
authors: R
authors: Deng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000494:pharmacology; D003663:Decision Trees; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008954:Models, Biological
chemical_list: D000911:Antibodies, Monoclonal
keywords: allometry scaling; monoclonal antibody; pharmacokinetics; species-invariant time method; target-mediated drug disposition