Predicting mAb Pharmacokinetics in Humans with a Minimal PBPK Model

Predicting mAb Pharmacokinetics in Humans with a Minimal PBPK Model

Monoclonal antibodies (mAbs) and their derivatives are a rapidly growing segment of the pharmaceutical industry’s pipeline. In fact, more than 40 mAbs and derivatives have been approved for a variety of therapeutic applications; around 500 mAbs and derivatives are currently in different stages of development. Monoclonal antibodies have pharmacokinetic (PK) properties that are quite distinct from that of small molecules. In this blog post, I’ll discuss how we developed a minimal physiologically based PK (PBPK) model that describes the pharmacokinetics of mAbs in humans.

What are monoclonal antibodies?

Antibodies are large (150 kDa) Y-shaped proteins that are produced by immune cells to defend the body against pathogens. A hallmark of antibodies is their ability to specifically bind to epitopes on their molecular targets. The ability of mAbs to bind epitopes has been harnessed by drug companies in the development of treatments for certain cancers and autoimmune diseases.

Monoclonal antibodies: not just “big chemicals”

Compared to small molecules, mAbs differ in their pharmacokinetic behavior in several key regards including:

  • Relatively poor cellular permeability
  • Minimal renal filtration
  • FcRn binding
  • Target-mediated drug disposition (TMDD)
  • Disposition via lymph

Cells take up mAbs via a complex process involving membrane invagination of plasma components (fluid-phase endocytosis). Once in cells, mAbs can be transported to the interstitial space, recycled to the blood, or degraded in subcellular lysosomes.The neonatal Fc receptor (FcRn) helps protect IgG from lysosomal degradation after endocytosis. It is the main reason for IgG’s extended half-life in the plasma.

Building a minimal PBPK model to describe the PK of mAbs in humans

Previous studies have presented PBPK models that describe the PK of mAbs in rodents. Likewise, this recent study used a minimal PBPK model to describe the disposition of mAbs in humans. However, it did not include important biological phenomena such as FcRn-mediated distribution and elimination. Our model addressed these important physiological aspects of mAb PK.

My colleagues, Drs. Linzhong Li and Masoud Jamei, and I used the Simcyp Simulator to simulate mAb PK in humans using a mechanistic minimal PBPK model. The body was divided into three compartments: plasma, tissue, and lymph with the tissue compartment being further sub-divided into vascular, endothelial, and interstitial spaces. The model accounted for the levels of both endogenous IgG and exogenous therapeutic mAbs in each compartment and sub-compartment. We used a Monte-Carlo sampling approach to simulate the concentrations of IgG and mAb in a virtual human population. The model also accounted for competition between native IgG and exogenous mAbs for FcRn binding in the endothelial space. We coupled TMDD models to the PBPK model to simulate the effects of binding targets in the plasma or interstitial space on mAb PK. To test the feasibility of our model, we simulated the PK of adalimumab and an anti-ALK1 antibody in a virtual population and compared the results to published clinical data.

Read more about this work in the AAPS Journal article, Simulation of Monoclonal Antibody Pharmacokinetics in Humans Using a Minimal Physiologically Based Model. According to the AAPS Journal’s editor-in-chief, Ho-Leung Fung, this article was one of the top 5 most downloaded articles in the 2nd half of 2014!

Want to learn more about using PBPK to conduct virtual clinical trials?

My colleagues, Drs. Karen Rowland Yeo and Suzanne Minton wrote an article “Conducting Virtual Trials Using PBPK To Drive More Precise Label Claims” in Clinical Leader. I hope that you’ll read it and let me know what you think in the comments section!

Iain Gardner

About the Author

Dr. Gardner has been at Certara since 2011. He leads the science team that is responsible for further developments of the population based physiologically based PK-PD Simulators to meet the needs of our consortium members.