Characterization and Interspecies Scaling of rhTNF-α Pharmacokinetics with Minimal Physiologically Based Pharmacokinetic Models

Abstract

Tumor necrosis factor- (TNF-) is a soluble cytokine and target of specific monoclonal antibodies (mAbs) and other biologic agents used in the treatment of inflammatory diseases. These biologics exert their pharmacological effects through binding and neutralizing TNF-, and thus they prevent TNF- from interacting with its cell surface receptors. The magnitude of the pharmacological effects is governed not only by the pharmacokinetics (PK) of mAbs, but also by the kinetic fate of TNF- We have examined the pharmacokinetics of recombinant human TNF- (rhTNF-) in rats at low doses and quantitatively characterized its pharmacokinetic features with a minimal physiologically based pharmacokinetic model. Our experimental and literature-digitalized PK data of rhTNF- in rats across a wide range of doses were applied to global model fitting. rhTNF- exhibits permeability rate-limited tissue distribution and its elimination is comprised of a saturable clearance pathway mediated by tumor necrosis factor receptor binding and disposition and renal filtration. The resulting model integrated with classic allometry was further used for interspecies PK scaling and resulted in model predictions that agreed well with experimental measurements in monkeys. In addition, a semimechanistic model was proposed and applied to explore the absorption kinetics of rhTNF- following s.c. and other routes of administration. The model suggests substantial presystemic degradation of rhTNF- for s.c. and i.m. routes and considerable lymph uptake contributing to the overall systemic absorption through the stomach wall and gastrointestinal wall routes of dosing. This report provides comprehensive modeling and key insights into the complexities of absorption and disposition of a major cytokine.

Interrelationships between Infliximab and Recombinant Tumor Necrosis Factor-αin Plasma Using Minimal Physiologically Based Pharmacokinetic Models

“…The PK of infliximab and rhTNF-a were first characterized with mPBPK models, and then both mPBPK models were combined and TMDD kinetic features added to assess the suppression of rhTNF-a by infliximab. The PK-related parameters for infliximab estimated from the initial modeling step and for rhTNF-a obtained from our companion study (Chen et al, 2017) were fixed in the subsequent model fitting for assessment of the interaction of infliximab and rhTNF-a.…”

“…The data set includes the PK of infliximab and rhTNF-a as well as their interaction, which are subject to different degrees of variability. Having PK-related parameters estimated first allowed characterization of infliximab binding and disposition with rhTNF-a (Chen et al, 2017).…”

“…The PK of rhTNF-a was previously described by Chen et al (2017) with an extended first-generation mPBPK model and a semimechanistic model for s.c. absorption. The model structure (Fig.…”

Characterization of concurrent target suppression by JNJ-61178104, a bispecific antibody against human tumor necrosis factor and interleukin-17A

“…This is considerably lower than some of the reported plasma half-life of rhTNF in rats. 42 , 43 While there is always uncertainty in model parameter estimates, it is important to note that all studies that studied the kinetics of rhTNF were conducted at concentration ranges substantially higher than the physiologically relevant levels. The saturable TNF receptor-mediated binding and disposition have been suggested to be a dominant elimination pathway for TNF.…”

ATLAS mPBPK: A MATLAB‐Based Tool for Modeling and Simulation of Minimal Physiologically‐Based Pharmacokinetic Models

“…Recently, Cao et al 3,4,7 and Cao and Jusko 3,4,7 introduced a number of generic frameworks of mPBPK models that adequately describe the kinetics of a large group of small and large molecules. So far these models have been used to explain different scenarios such as interspecies scaling, 8,28 modeling sex differences in PK, and combined drug effects [29][30][31] as well as in combination with pharmacodynamic models to investigate drug effects. 20 In this tutorial, we present a MATLAB-based tool for the modeling and simulation of mPBPK models (ATLAS mPBPK).…”