O05_02

The effect of food on pharmacokinetics of acotiamide for the treatment of functional dyspepsia

Kazuyoshi YOSHII *, Ryotaro IWAKIRI, Ryoko TODA

Ethical drug research, ZERIA Pharmaceutical Ltd., Co.
( * E-mail: kazuyoshi-yoshii@zeria.co.jp)

It is known that the pharmacokinetics of drugs can be altered by the meal itself or the physiological changes caused by the meal. In drug development, changes in pharmacokinetics due to meals can influence the design of clinical trials, making it important to evaluate the effect of meals in advance. Japanese guidelines recommend clinical trials to assess the effect of meals using the final formulation, and at that timing, various data are acquired, thus considering mechanism-based investigations such as physiologically based pharmacokinetic models is deemed important. Initially, machine learning models were examined for the purpose of predicting the effects of meals. Due to the low prediction accuracy of machine learning models using structural features, it was inferred that predicting the effects of meals based solely on structural information is difficult at the current time. Next, the impact of physiological changes caused by meals on pharmacokinetics was investigated using pharmacokinetic models. Within the range of compounds studied, it was found that changing the physiological parameters of the pharmacokinetic model alone was not sufficient to predict the effects of meals. Lastly, a case study was conducted using the pharmacokinetic model to investigate the effects of meals on the functional dyspepsia treatment drug, acotiamide. Compared to fasting administration, pre-meal administration of acotiamide reported an increase in Cmax, and post-meal administration reported a decrease in AUC. The causes of these changes were considered to be acotiamide's promotive effect on gastric emptying and the inhibitory effect of meal components on absorption, hence a sensitivity analysis of related parameters was conducted. The sensitivity analysis showed that by altering the gastric transit time and membrane permeation rate, it was possible to simulate the effects of meals on acotiamide. Therefore, at the current stage, a case-by-case investigation using pharmacokinetic models is considered effective for understanding the effects of meals on the pharmacokinetics of drugs. Acotiamide is administered before meals to relieve symptoms of functional dyspepsia such as postprandial fullness, and pre-meal administration shows positive effects, suggesting that taking it before meals could lead to more effective symptom relief.