caa a22 4500 605534179 CHVBK 20210128100841.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s10928-014-9402-0 doi (NATIONALLICENCE)springer-10.1007/s10928-014-9402-0 Development of a physiologically based pharmacokinetic model for a domain antibody in mice using the two-pore theory [Elektronische Daten] [Armin Sepp, Alienor Berges, Andrew Sanderson, Guy Meno-Tetang] 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 10mg/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. Springer Science+Business Media New York, 2015 Domain antibody nationallicence Two-pore theory nationallicence Physiologically based pharmacokinetics nationallicence Sepp Armin BioPharm Innovation, Biopharm R&D, GlaxoSmithKline, Gunnels Wood Road, SG1 2NY, Stevenage, UK aut Berges Alienor Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, UB11 1BT, Middlesex, UK aut Sanderson Andrew BioPharm Innovation, Biopharm R&D, GlaxoSmithKline, Gunnels Wood Road, SG1 2NY, Stevenage, UK aut Meno-Tetang Guy Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, UB11 1BT, Middlesex, UK aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/2(2015-04-01), 97-109 1567-567X 42:2<97 2015 42 10928 https://doi.org/10.1007/s10928-014-9402-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-014-9402-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sepp Armin BioPharm Innovation, Biopharm R&D, GlaxoSmithKline, Gunnels Wood Road, SG1 2NY, Stevenage, UK aut NATIONALLICENCE 700 1- Berges Alienor Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, UB11 1BT, Middlesex, UK aut NATIONALLICENCE 700 1- Sanderson Andrew BioPharm Innovation, Biopharm R&D, GlaxoSmithKline, Gunnels Wood Road, SG1 2NY, Stevenage, UK aut NATIONALLICENCE 700 1- Meno-Tetang Guy Clinical Pharmacology, Modelling and Simulation, GlaxoSmithKline, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, UB11 1BT, Middlesex, UK aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/2(2015-04-01), 97-109 1567-567X 42:2<97 2015 42 10928