Hiroyuki Takita (1,2), Adam Darwich (1), Amais Ahmad (1), Amin Rostami-Hodjegan (1,3)
(1) Centre for Applied Pharmacokinetics Research, University of Manchester, Manchester, UK, (2) Laboratory for Safety Assessment and ADME, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan, (3) Simcyp Limited (A Certara Company), Sheffield, UK
Introduction: The gastrointestinal (GI) tract has been the focus of several potential therapeutic target linked to metabolic diseases, cancer, inflammatory disorders etc [1]. However, development drugs for such targets is challenging because of the complex and dynamic physiology of gut wall (e.g. the rapid turnover of the enterocytes [2]).
The enterocytes are produced in the crypt at the base of the villi in the intestine, and then migrate up the crypt-villous axis, where the turnover will be governed by apoptosis or shedding into the gut lumen at the tip of the villi. The average time from enterocyte generation to shedding is reported to be 3 and half days (range 1-7 days). This is much faster turnover cycle than other types of tissue cells. In addition, the turnover rate of the enterocyte is reduced to less than one day in some diseases such as untreated coeliac disease [3]. In the field of PK/PD modelling, turnover of target protein or drug dissociation rate constant from target protein (koff) has been studied and considered as a rate limiting step of pharmacodynamics [4][5]. However, to the best of our knowledge, most of the models either ignored the turnover of the enterocytes itself or used a lumped cell-protein turnover, which could lead to a different PD effect in case enterocyte turnover is a rate limiting step. Moreover, these hybrid turnover functions cannot account for changes taking place in pathophysiology when disease affects part of the hybrid function.
Recently, we have shown that the nested-enzyme-within-enterocyte (NEWE) turnover model, which incorporates turnover for both enterocyte and metabolic enzyme, can capture the drug-drug interactions at gut wall in the presence of disease affecting cell turnover [6]. Here, we expanded the on the work and provide a general framework to investigate the impact of enterocyte turnover on dynamics of pharmacological effects on the gut wall under different conditions.
Objectives:
- l Develop a nested-target-within-enterocyte (NTWE) turnover model, which is a new theoretical PK/PD framework for pharmacological effects on gut wall in health and disease
- l Evaluate the impact of enterocyte turnover on time course of pharmacological effects on the GI tract through simulations in an array of realistic parameter ranges
- l Summarize information in the form of principles guiding the development of drugs for targets in the gut wall
Methods: The compartmental NTWE model consisted of the intestinal lumen, enterocyte, lamina propria, liver and central compartment. In the enterocyte compartment, drug association and dissociation with the PD target protein was described using binding rate constants. The degree of pharmacodynamics effect was assumed to be in proportion to the amount of target protein or drug-target protein complex. The turnover of enterocytes was expressed by initializing the parameters in the enterocyte compartment at the rate of enterocyte turnover. Representative values and probability distributions of parameters, such as turnover rate of the enterocytes, turnover of target protein and binding kinetic constants, were obtained from the literature and used to inform the simulation study. The PD index, defined as the index of enterocyte turnover contribution on pharmacodynamics, was calculated as a ratio of the effect in the model considering enterocyte turnover and without considering enterocyte turnover.
Representative values for each parameter were defined based on their probability distributions. Parameters were randomly sampled to generate multiple parameter sets. Simulations were performed based on these parameter sets and results were analysed to evaluate the impact of enterocyte turnover on PD effect.
Results: When enterocyte lifespan was within the range observed in healthy volunteer (1-7 days), the reduction in PD index was observed when koff was in the low range (0.003 h-1, strong/irreversible target binding), and half-life of target protein was long (200 hours). More importantly, in case of diseased population, where enterocyte lifespan was shorter (0.25 days), a reduction was observed in PD index even at higher values of koff (< 0.3 h-1), which is in the range of reversible drug-target binding.
Conclusions: The contribution of enterocyte turnover should be incorporated into the mechanistic PK/PD model in the case of irreversible inhibition of target proteins particularly for disease states where enterocyte turnover rate is altered.
References:
[1] Filipski KJ et al. Curr Top Med Chem. 2013;13(7):776-802.
[2] Darwich AS et al. Drug Metab Dispos. 2014 Dec;42(12):2016-22.
[3] Brigic E et al. Mater Sociomed. 2012;24(4):242-7.
[4] Jusko WJ. J Pharm Sci. 2013 Sep;102(9):2930-40.
[5] Copeland RA et al. Nat Rev Drug Discov. 2006 Sep;5(9):730-9.
[6] Darwich AS et al. Eur J Pharm Sci. 2019
Reference: PAGE 28 (2019) Abstr 9116 [www.page-meeting.org/?abstract=9116]
Poster: Methodology - New Modelling Approaches