ArticleCPT: pharmacometrics & systems pharmacology2020
Application of the Nested Enzyme-Within-Enterocyte (NEWE) Turnover Model for Predicting the Time Course of Pharmacodynamic Effects.
Article in CPT: pharmacometrics & systems pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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.
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