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Development of a physiologically based pharmacokinetic model for a domain antibody in mice using the two-pore theory

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Abstract

Domain antibodies (dAbs) are the smallest antigen-binding fragments of immunoglobulins. To date, there is limited insight into the pharmacokinetics of dAbs, especially their distribution into tissues and elimination. The objective of this work was to develop a physiologically-based pharmacokinetic model to investigate the biodisposition of a non-specific dAb construct in mice. Following a single IV administration of 10 mg/kg dummy dAb protein to twenty four female mice, frequent blood samples were collected and whole body lateral sections were analyzed by quantitative whole-body autoradiography. The model is based on the two-pore hypothesis of extravasation where organ-specific isogravimetric flow rates (Jorg,ISO) and permeability-surface area products (PSorg) are expressed as linear functions of the lymph flow rate (Jorg) and the kidney compartment is modified to account for glomerular filtration of dAb. As a result, only Jorg, glomerular filtration coefficient and the combined volume of Bowman’s capsule, proximal and distal renal tubules and loop of Henle were optimized by fitting simultaneously all blood and organ data to the model. Our model captures the pharmacokinetic profiles of dAb in blood and all organs and shows that extravasation into interstitial space is a predominantly diffusion-driven process. The parameter values were estimated with good precision (%RMSE ≈ 30) and low cross-correlation (R2 < 0.2). We developed a flexible model with a limited parameter number that may be applied to other biotherapeutics after adapting for size-related effects on extravasation and renal elimination processes.

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Acknowledgments

Valeriu Damian-lordache and Thuy Tran from GlaxoSmithKline for their useful comments on the manuscript

Conflict of interest

Armin Sepp, Alienor Berges, Andrew Sanderson, and Guy Meno-Tetang are all employees of GlaxoSmithKline Plc.

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Authors and Affiliations

  1. BioPharm Innovation, Biopharm R&D, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Armin Sepp & Andrew Sanderson

  2. Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, Middlesex, UB11 1BT, UK

    Alienor Berges & Guy Meno-Tetang

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  1. Armin Sepp
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  2. Alienor Berges
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  4. Guy Meno-Tetang
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Correspondence to Guy Meno-Tetang.

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Sepp, A., Berges, A., Sanderson, A. et al. Development of a physiologically based pharmacokinetic model for a domain antibody in mice using the two-pore theory. J Pharmacokinet Pharmacodyn 42, 97–109 (2015). https://doi.org/10.1007/s10928-014-9402-0

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  • DOI: https://doi.org/10.1007/s10928-014-9402-0

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