Byungjeong Song, Jung-woo Chae, Byoungyo Lee, Hyunmoon Back, Jaeyeon Lee, Hwi-yeol Yun, Kwang-il Kwon
College of pharmacy, Chungnam National University, Daejeon, Korea
Objectives: The purpose of this study was to establish a simplified-ACAT (advanced compartmental absorption and transit) model of specific angiotensin receptor blocker (ARB) and to applicate this model to human.
Methods: For building the simplified-ACAT model for ARB, rat whole body autoradiography (WBA) data after oral administration was used and for application of the model to human, phase I clinical data of 30 volunteers was used. For applying the simplified-ACAT model to human, only those parameters which represent organ size were scaled up for human. Modeling process was carried out using nonlinear mixed effect modeling (NONMEMⓇ) program. For describing unconventional disposition of drugs to liver, Michaelis-Menten kinetics and fractal kinetics which can explain non-linear kinetics of drugs were used.
Results: : In total, over 60 radioactive concentrations from organ samples in rats and 398 plasma samples in human were collected after oral administration. The final simplified-ACAT model which is composed of multiple compartment includes stomach, small intestine, large intestine, liver and plasma were successfully established with almost 30 estimated parameters. The kinetics of drugs in plasma was well explained with this simplified-ACAT model. But the non-linear kinetics in the liver compartment still ongoing.
Conclusions: This approach may facilitate prediction of human ARB pharmacokinetics, and may be extended to other study, for examples, drug-drug interaction study. As a matter of fact, this simplified-ACAT model still have limits. Nevertheless, this model appears to be promising and should be further evaluated.
References:
[1] Grant Langdon, Ivelina Gueorguieva, Leon Aarons, Mats Karlsson. Linking preclinical and clinical whole-body physiologically based pharmacokinetic models with prior distributions in NONMEM. Eur J Clin Pharmacol (2007) 63:485-498
[2] Benjamin Guiastrennec, David P. Sonne, Oskar Alskar et al., Mechanism-based modelling of gastric emptying and bile release in response to caloric intake. PAGE 2014
Reference: PAGE 24 (2015) Abstr 3386 [www.page-meeting.org/?abstract=3386]
Poster: Drug/Disease modeling - Absorption & PBPK