2017 - Budapest - Hungary

PAGE 2017: Other Topics
Miro Eigenmann

Therapeutic antibody concentrations at the biophase

Miro J. Eigenmann (1), Tine V. Karlsen (2), Ben-Filippo Krippendorff (1), Michael B. Otteneder (1), Olav Tenstad (2) and Helge Wiig (2)

(1) Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Centre Basel, Switzerland, (2) Department of Biomedicine, University of Bergen, Norway

Objective: Concentrations of monoclonal antibodies in the different tissue compartments, vascular, interstitial and cellular, are very heterogeneous [1, 2]. PK measurements in the tissue interstitial spaces are very challenging [3] and often lacking for macromolecules. In this work we strive to improve the prediction of the interstitial PK of monoclonal antibodies in tissues using a combination of tailored in vivo studies and a PBPK modeling approach.

Methods:  Tracer distribution studies were performed in mice in order to assess extracellular (51Cr-EDTA), residual plasma (125I-albumin) and derive interstitial volumes of individual tissues. In the same mouse strain, a biodistribution study of an untargeted IgG monoclonal antibody was conducted after i.v. injection of a 10mg/kg dose. Skin and muscle samples were subject to a tissue centrifugation method [4] in order to isolate native interstitial fluid and measure concentrations therein. All newly measured parameters and data were used to estimate tissue subcompartment concentrations and integrated into a PBPK model in order to predict interstitial tissue concentrations of mAbs.

Results: The PK showed a biphasic profile in plasma with a Cmax of ~210mg/mL and clearance of ~9mg/kg/d. Residual plasma fractions are high in well perfused tissues (e.g. lung=0.137) whereas lower in tissues with less blood perfusion (e.g. muscle=0.009). The interstitial volume fraction was found to be highest in skin (0.431). Corrections with tissue volume fractions enabled us to derive expected extravascular and interstitial concentrations in tissues. Measured interstitial concentrations in skin and muscle reach concentrations of about 50% of plasma concentration. The established PBPK model allowed an accurate description of the derived concentrations in the different tissue subcompartments.

Conclusion: Interstitial concentrations are highly tissue specific, dependent on the underlying capillary structure of the tissues [5, 6]. We hypothesize, that concentrations in tissues with discontinuous capillaries (e.g. liver, spleen and bone marrow) might even be equal to plasma concentrations. High concentrations (~50% of Cpla) were found in skin and muscle, tissues with continuous capillaries. In kidney and brain however, extravascular concentrations seem negligible. Integration of such data and parameter values into a PBPK model allows a physiologically more realistic and accurate description of the PK in the tissue interstitial space. 

[1] Lobo, E.D., R.J. Hansen, and J.P. Balthasar, Antibody pharmacokinetics and pharmacodynamics. Journal of pharmaceutical sciences, 2004. 93(11): p. 2645-68.
[2] Shah, D.K. and A.M. Betts, Antibody biodistribution coefficients: inferring tissue concentrations of monoclonal antibodies based on the plasma concentrations in several preclinical species and human. mAbs, 2013. 5(2): p. 297-305.
[3] Wiig, H. and M.A. Swartz, Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiological reviews, 2012. 92(3): p. 1005-60.
[4] Wiig, H., K. Aukland, and O. Tenstad, Isolation of interstitial fluid from rat mammary tumors by a centrifugation method. American journal of physiology. Heart and circulatory physiology, 2003. 284(1): p. H416-24.
[5] Sarin, H., Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability. Journal of angiogenesis research, 2010. 2: p. 14.
[6] Rippe, B. and B. Haraldsson, Transport of macromolecules across microvascular walls: the two-pore theory. Physiological reviews, 1994. 74(1): p. 163-219.  

Reference: PAGE 26 (2017) Abstr 7225 [www.page-meeting.org/?abstract=7225]
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