Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics

Abstract

Therapeutic proteins (TPs) have ranked among the most important and fastest-growing classes of drugs in the clinic, yet the development of successful TPs is often limited by unsatisfactory efficacy. Understanding pharmacokinetic (PK) characteristics of TPs is key to achieving sufficient and prolonged exposure at the site of action, which is a prerequisite for eliciting desired pharmacological effects. PK modeling represents a powerful tool to investigate factors governing in vivo disposition of TPs. In this mini-review, we discuss many state-of-the-art models that recapitulate critical processes in each of the absorption, distribution, metabolism/catabolism, and excretion pathways of TPs, which can be integrated into the physiologically-based pharmacokinetic framework. Additionally, we provide our perspectives on current opportunities and challenges for evolving the PK models to accelerate the discovery and development of safe and efficacious TPs. SIGNIFICANCE STATEMENT: This minireview provides an overview of mechanistic pharmacokinetic (PK) models developed to characterize absorption, distribution, metabolism, and elimination (ADME) properties of therapeutic proteins (TPs), which can support model-informed discovery and development of TPs. As the next-generation of TPs with diverse physicochemical properties and mechanism-of-action are being developed rapidly, there is an urgent need to better understand the determinants for the ADME of TPs and evolve existing platform PK models to facilitate successful bench-to-bedside translation of these promising drug molecules.

Fig. 1.

Schematic of ADME models for TPs. (A) Structure of a whole-body PBPK model for TPs’ disposition (adapted from Shah and Betts, 2012). Organs are represented by rectangular compartments connected via blood flows (solid arrows) and lymphatic flows (dashed arrows). Organ-specific distribution or elimination mechanisms will be elaborated below for tumor, brain, eye, kidney, and skin. (B) Diagram of tissue-level models that characterize distribution of TPs for a typical organ (adapted from Sepp et al., 2019), based on one-pore (left panel) or two-pore (right panel) theories. A tissue is divided into vascular, endosomal, and interstitial spaces. Diffusion is denoted by solid arrows and convection by dashed arrows. Specially curved arrows stand for the isogravimetric flow. (C) Representation of the Krogh cylinder tumor model (adapted from Cilliers et al., 2016). The area in red refers to tumoral vasculature, from where TPs can escape via diffusion. Transport of TPs can also be driven by surface uptake from an adjacent organ. (D) Structure of the brain PBPK model. Brain is divided into vascular, BCSFB, BBB, CSF, and parenchymal compartments. (E) Structure of the ocular PBPK model. Regions in the eye include cornea, ICB, lens, retina, choroid, sclera, aqueous humor, and vitreous humor. Black solid arrows represent blood flows, green dashed arrows represent convective flows, and red double-headed arrows represent diffusion processes. (F) Representation of endosomal models that characterize FcRn interaction with IgGs (adapted from Chen and Balthasar, 2012). The panel on the left-hand side assumes equilibrium binding between IgGs and FcRn. The panel on the right-hand side adopts a catenary model, where endosomal subcompartments have pH ranging from 7.4 to 6.0. (G) Representation of a TMDD model for a membrane-bound antigen in the tumor compartment. The free receptor has its inherent turnover rate and is allowed to bind to TPs in the extracellular space of a solid tumor. (H) Schematic of renal elimination of TPs (adapted from Rabkin and Dahl, 1993). Following glomerular filtration, TPs are internalized into tubular cells for degradation or eliminated into the urine. TPs in the postglomerular peritubular capillaries can also be endocytosed, followed by intracellular degradation. (I) Structure of a SC absorption model (adapted from Hu and D'Argenio, 2020). ICB, iris-ciliary body; L.G., int large intestine; SC, subcutaneous; S.M., small intestine.