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

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 (R(2) < 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.

Cross-species/cross-modality physiologically based pharmacokinetics for biologics: 89Zr-labelled albumin-binding domain antibody GSK3128349 in humans

“…In summary, we have demonstrated that the biologics PBPK framework we established using a series of inert tracer proteins in rodents 13 , 14 provided good to satisfactory extrapolation to humans without significant further parameterization. The resulting framework can be extended and adapted to more complex and clinically relevant scenarios for informative insight, as described for ibalizumab.…”

“…In the case of proteins, the most flexible approach is often described in terms of two-pore hypothesis proposed by Rippe and Haraldsson 12 where extravasation is linked to the lymph flow and treated as a filtration-diffusion process taking place at the paracellular vascular pores. Previously we showed in theory and practice that the filtration and diffusion-driven fluxes can be treated as linear functions of the lymph flow rate in such systems, 13 and followed up with an extensive study in mice and rats where the same framework was applied to a number of different biologics to estimate the organ-specific fractional lymph flow rates as the only empirically fitted global parameters. 14 …”

PBPK Modeling of Slightly Soluble Silver Nanomaterials and Regulatory Acceptance

“…The ratio does not describe a parallel pipe configuration nor does it represent a known physical. Other PBTK models [ 17,18 ] utilize , which is the residence time for every traverse through the organ. In the ETH model, the extremes of long residence times (lower flow rate, larger organ blood volume) and short ones (higher flow rate, smaller organ blood volume) are not fully expressed, and of note relative to argyria, the rat skin compartment is at the lower flowrate/larger volume extreme (see Table S1 of ref.…”

A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim

“…The aim of the current work is to extend the established PBPK model in PK-Sim [ 33 – 36 ] which was designed for small molecule drugs, to allow simulation of macromolecules such as protein therapeutics in one comprehensive pharmacokinetic modeling framework. The current implementation of the model replaces the unpublished generic protein PBPK model available in PK-Sim since version 4.2 providing an updated parameterization using new experimental data [ 29 ] and an explicit representation of drug–FcRn binding. The model becomes part of the open source Open Systems Pharmacology Suite ( www.open-systems-pharmacology.org ).…”