Application of the Nested Enzyme‐Within‐Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects

Abstract

The gut wall consists of many biological elements, including enterocytes. Rapid turnover, a prominent feature of the enterocytes, has generally been ignored in the development of enterocyte‐targeting drugs, although it has a comparable rate to other kinetic rates. Here, we investigated the impact of enterocyte turnover on the pharmacodynamics of enterocyte‐targeting drugs by applying a model accounting for turnover of enterocytes and target proteins. Simulations showed that the pharmacodynamics depend on enterocyte lifespan when drug‐target affinity is strong and half‐life of target protein is long. Interindividual variability of enterocyte lifespan, which can be amplified by disease conditions, has a substantial impact on the variability of response. However, our comprehensive literature search showed that the enterocyte turnover causes a marginal impact on currently approved enterocyte‐targeting drugs due to their relatively weak target affinities. This study proposes a model‐informed drug development approach for selecting enterocyte‐targeting drugs and their optimal dosage regimens.

Utility of PBPK Modeling in Predicting and Characterizing Clinical Drug Interactions

“…The degradation rates can differ between the liver and intestine, most likely due to differences in the cellular turnover of hepatocytes relative to enterocytes (Yang et al, 2008). The overall life span of enterocytes (approximately 3.5 days) is relatively short compared to that of hepatocytes (200 -300 days) and as such, has a direct effect on the half-lives of drug metabolizing enzymes expressed within each cell (Wood, 1971;Duncan et al, 2009;Takita et al, 2020). Simcyp TM and PK-Sim ® currently utilize 0.0193 h -1 (T1/2 = 36 hours) and 0.030 h -1 (T1/2 = 23 hours) as the degradation rates of CYP3A4 in the liver and intestine, respectively (Tseng et al, 2021;Loer et al, 2022).…”