Tatiana Zasedateleva (1), Stephan Schaller (1), Wilhelmus E. A. de Witte (1)
(1) ESQlabs GmbH, Saterland, Germany
Introduction:
Large molecule drugs, including monoclonal antibodies and antibody-drug conjugates, bind with high affinity and specificity to their targets and have long pharmacokinetic half-lives. All of these properties increase their therapeutic effects but also introduce a propensity to non-linear pharmacokinetics due to extensive target binding, known as Target-Mediated Drug Disposition (TMDD) [1–3]. TMDD describes that in many scenarios, drug-target binding may have an impact not only on the drug’s pharmacodynamics but also on its pharmacokinetics [4]. However, many targets are expressed in tissues rather than in plasma, which implies a much lower impact of target binding on drug plasma concentrations compared to the typically simplified model with drug-target binding in the central compartment, especially when the drug-target interaction occurs in smaller organs with lower perfusion. The potential for localized TMDD, along with the limited impact of target binding in tissues on plasma concentrations, renders typical TMDD parameters, such as the target concentration and target turnover, relevant for many drug discovery and drug development projects, even if non-linear pharmacokinetics are not observed during routine pharmacokinetic studies.
Objectives:
This study aims to collect physiological values for TMDD parameters in tissues, encompassing various targets from different sources and species. Based on these obtained values, we seek to enhance our understanding of each parameter’s significance in this system and identify the likelihood of local depletion of drug concentrations for biologics whose target is expressed in the tissue.
Methods:
Literature studies were conducted to gather typical values for target concentration, target degradation, and drug-target complex internalization rate constants. These values were categorized based on the origin of parameter values and by the species, the prevalent localizations of the targets in the body, organs, or compartments for the model estimates. Simulations were performed using a whole-body Physiologically-Based Pharmacokinetic model (PK-Sim v11.0), with the target expressed in the interstitial space of the heart or muscle and the drug simulated as a large molecule in the large molecule model [5].
Results:
Across various species, target concentrations have a similar distribution, with a median of around 10 nM. Moreover, the soluble targets typically exhibit lower concentrations than targets expressed in tissue cell membranes and intracellularly. The degradation rate constants generally exceed internalization rate constants in most species, resulting in kint/kdeg ratios below 1. Additionally, the degradation rate constants are higher for soluble targets, while membrane-bound targets expressed in tissues show higher internalization rates. The kint/kdeg ratios for soluble targets are predominantly below 1, while these ratios are distributed around 1 for membrane targets.
In many of the simulated scenarios, local depletion of the drug was observed, as evidenced by a significant decrease in interstitial concentrations and, consequently, in target occupancy, with increasing target concentrations and turnover. However, plasma concentrations remained minimally affected even with the target expressed in the large muscle organ. Furthermore, even when the plasma clearance was affected by local TMDD due to the high tissue volume of the muscle, the absence of the classical non-linear pattern in plasma curves persisted.
Conclusions:
This study sheds light on the impact of target concentration and target turnover on local drug concentrations and target occupancy within the tissue interstitial space in physiologically realistic scenarios. These findings emphasize the importance of evaluating TMDD parameters and raise questions regarding the sufficiency of relying on conventional plasma measurements in cases with a potential of localized TMDD.
References:
[1] J.T. Ryman, B. Meibohm, Pharmacokinetics of Monoclonal Antibodies, CPT Pharmacomet. Syst. Pharmacol. 6 (2017) 576–588. https://doi.org/10.1002/psp4.12224.
[2] Y. Cao, W.J. Jusko, Incorporating target-mediated drug disposition in a minimal physiologically-based pharmacokinetic model for monoclonal antibodies, J. Pharmacokinet. Pharmacodyn. 41 (2014) 375–387. https://doi.org/10.1007/s10928-014-9372-2.
[3] A. Samantasinghar, N.P. Sunildutt, F. Ahmed, A.M. Soomro, A.R.C. Salih, P. Parihar, F.H. Memon, K.H. Kim, I.S. Kang, K.H. Choi, A comprehensive review of key factors affecting the efficacy of antibody drug conjugate, Biomed. Pharmacother. 161 (2023) 114408. https://doi.org/10.1016/j.biopha.2023.114408.
[4] G. Levy, Pharmacologic target-mediated drug disposition, Clin. Pharmacol. Ther. 56 (1994) 248–252. https://doi.org/10.1038/clpt.1994.134.
[5] C. Niederalt, L. Kuepfer, J. Solodenko, T. Eissing, H.-U. Siegmund, M. Block, S. Willmann, J. Lippert, A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim, J. Pharmacokinet. Pharmacodyn. 45 (2018) 235–257. https://doi.org/10.1007/s10928-017-9559-4.
Reference: PAGE 32 (2024) Abstr 11007 [www.page-meeting.org/?abstract=11007]
Poster: Drug/Disease Modelling - Other Topics