Simulation of monoclonal antibody pharmacokinetics in humans using a minimal physiologically based model

AAPS J. 2014 Sep;16(5):1097-109. doi: 10.1208/s12248-014-9640-5. Epub 2014 Jul 9.


Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further sub-divided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data.

MeSH terms

  • Adalimumab
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / blood
  • Antibodies, Monoclonal / pharmacokinetics*
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / blood
  • Antibodies, Monoclonal, Humanized / pharmacokinetics*
  • Computer Simulation*
  • Drug Administration Routes
  • Drug Dosage Calculations
  • Feasibility Studies
  • Half-Life
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immunoglobulin G / metabolism
  • Lymph / metabolism
  • Metabolic Clearance Rate
  • Models, Biological*
  • Monte Carlo Method
  • Permeability
  • Protein Binding
  • Receptors, Fc / metabolism


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Histocompatibility Antigens Class I
  • Immunoglobulin G
  • Receptors, Fc
  • ascrinvacumab
  • Adalimumab
  • Fc receptor, neonatal