Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models
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The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition—identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)—is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice.
KeywordsmAb disposition PBPK Extravasation rate-limited tissue model Classical compartment model
Ludivine Fronton and Sabine Pilari acknowledge financial support from the Graduate Research Training Program PharMetrX: Pharmacometrics & Computational Disease Modeling, Freie Universität Berlin and Universität Potsdam, Germany (http://www.PharMetrX.de). Fruitful discussions with the early DMPK, DMPK and M&S teams (F. Hoffmann-La Roche Ltd, pRED, Pharmaceutical Sciences, Basel, Switzerland) and Frank-Peter Theil and Jay Tibbits (UCB Pharma, Belgium) are kindly acknowledged.
- 15.Azzopardi N, Lecomte T, Ternant D, Piller F, Ohresser M, Watier H, Gamelin E, Paintaud G (2010) Population pharmacokinetics and exposition-PFS relationship of cetuximab in metastatic colorectal cancer. Population Approach Group MeetingGoogle Scholar
- 16.Lammertsvan Bueren J, Bleeker W, Bogh H, Houtkamp M, Schuurman J, van de Winkel J, Parren P (2006) Effect of target dynamics on pharmacokinetics of a novel therapeutic antibody against the epidermal growth factor receptor: implications for the mechanisms of action. Cancer Res 66(15):7630CrossRefGoogle Scholar
- 25.Garg A (2007) Investigation of the role of FcRn in the absorption, distribution, and elimination of monoclonal antibodies. Ph.D. thesis, Faculty of the Graduate School of State University of New York at BuffaloGoogle Scholar
- 33.Lagarias J, Reeds JA, Wright MH, Wright PE (1998) Convergence properties of the nelder-mead simplex method in low dimensions. J Optim Theory Appl 9(1):112Google Scholar
- 40.EMEA (2013) Summary of product characteristics of cetuximab Google Scholar
- 41.EMEA (2012) Summary of product characteristics of infliximabGoogle Scholar
- 42.EMEA (2013) Summary of product characteristics of rituximabGoogle Scholar
- 43.EMEA (2013) Summary of product characteristics of trastuzumabGoogle Scholar
- 44.EMEA (2013) Summary of product characteristics of golimumabGoogle Scholar
- 45.EMEA (2013) Summary of product characteristics of tocilizumabGoogle Scholar
- 46.Huisinga W, Solms A, Fronton L, Pilari S (2012) Modeling inter-individual variability in physiologically-based pharmacokinetics and its link to mechanistic covariate modeling. CPT 1:e4Google Scholar