Category: Clinical Pharmacology
Purpose: Orally disintegrating tablets (OD tablets) are drugs that can be taken without water because that they dissolve quickly in the oral cavity.OD tablets are easy dosage form to take, so they have been developed for various drugs.The aim of this study is to develop a simulation approach for pharmacokinetics of OD tablets. We must pass both with water and without water bioequivalence studies (BE studies) for OD tablets in Japan, so it is important to know the behavior of gastrointestinal under condition dosing without water. However, there are still many questions regarding the change of the gastrointestinal condition under dosing without water. This time, we studied the effect of “stomach transit time” and “percent fluid in small intestine (SI)” using GastroPlusTM when dosing without water.
Methods: First, we conducted BE studies to human both under dosing with and without water for 6 drugs that were BCS Class I or II. When we dosed OD tablets with water, the water volume was 150 ml in these tests. And, when we dosed them without water, we swallowed them with saliva in the oral cavity. Then, we analyzed plasma concentrations of each drug, and compared between Cmax of with water and Cmax of without water. Second, in order to know the behavior of gastrointestinal under condition dosing without water, we set the basic models for 6 drugs based on their plasma concentrations under dosing with water using GastroPlusTM. The parameters of the basic models were set that the stomach transit time were 0.25 hours, and the percent fluid in SI was 40%. Third, we performed parameter sensitivity analysis (PSA) of the stomach transit time and the percent fluid in SI. The range of PSA were set that the stomach transit time were from 0.08 hours to 4 hours, and the percent fluid in SI was from 3% to 40%. Finally, we analyzed those models by setting the stomach transit time of 1 hour or the percent fluid in SI of 10%. Furthermore, we analyzed those models by changing both of them.
Results: As a result of BE studies, observed without water / with water ratio of Cmax were from 0.78 to 0.96, and Tmax of “without water”- Tmax of “with water” were from -0.07 hours to +1.30 hours (Table.1). All drugs reduced Cmax, and 5 drugs delayed Tmax. Then, as a result of PSA analysis at the stomach transit time, it had an effect on Cmax except for one drug. In the case of PSA analysis in the percent fluid in SI, it had an effect on Cmax of BCS Class Ⅱ drugs. On the other hand, it didn’t have an effect on Cmax of BCS Class Ⅰ drugs. We considered that Cmax of BCS Class Ⅱ drugs was very affected by percent fluid in SI because of their low solubility. As the result of both PSA on 6 drugs, the proper setting values of stomach transit time were between 0.5 - 4 hour and percent fluid in SI were between 8 - 30% in order to simulate the observed Cmax when dosing without water. From this result, we decided that the stomach transit time was 1 hour and the percent fluid in SI was 10% when we simulated at dosing without water. Finally, as the simulation result of changing both the stomach transit time and the percent fluid in SI, 4 drugs were close to the observed Cmax when dosing without water, but 2 drugs were not close to them(Table.2). It is thought that one of the reasons of this inconsistency is the difference of the stomach transit time between drug formulations.
Conclusion: When we dose OD tablets without water, Cmax was reduced and Tmax was delayed. It is estimated that stomach transit time is delayed and the amount of water in the gastrointestinal tract is reduced. It is suggested that we need to consider the stomach transit time and percent fluid in SI when we analyze OD tablets at dosing without water using GastroPlusTM. There is a possibility that the proper value of stomach transit time is 1 hour and percent fluid in SI is 10% for simulation of dosing without water . In this study, we targeted at BCS Class Ⅰ and Ⅱ drugs. So we study continuously various drugs like BCS Class Ⅲ or Ⅳ.
Yoko Kobayashi– Kyoto, Kyoto, Japan
Kanako Shimizu– Kadomashi, Osaka, Japan
Motoki Onishi– Kyoto, Kyoto, Japan
Kozo Tagawa– Kyoto, Kyoto, Japan
Hidetoshi Hashizume– Kyoto, Kyoto, Japan
Kazuhide Imagaki– Kyoto, Kyoto, Japan