Hyun A Lee (1,2), Kyeong-Ryoon Lee (3), Seong-Bok Jang (4), Kyung-Sang Yu (1), Howard Lee (1,2)
(1) Seoul National University College of Medicine and Hospital, Korea, (2) Graduate School of Convergence Science and Technology, Seoul National University, Korea, (3) Korea Research Institute of Bioscience and Biotechnology, Korea, (4) Yuhan Corporation, Korea
Introduction: YH4808 is a highly potent, selective and reversible potassium-competitive acid blocker of the H+/K+-ATPase under development to treat gastric acid-related diseases. The pharmacokinetics of YH4808 was dose-proportional in humans after a single oral dose at 30-800 mg. However, the systemic exposure to YH4808 decreased after multiple oral administrations, particularly at higher doses (200 and 400 mg) [1]. The reduced solubility of YH4808 caused by elevated intragastric pH after treatment with YH4808 was suggested as the main cause of the reduced exposure. This hypothesis was supported by a physiologically-based pharmacokinetic modeling and simulation analysis [2].
Objectives: To develop a pharmacokinetic and pharmacodynamic model to quantitatively evaluate the mutual relationships between the plasma concentrations of YH4808 and the time course of intragastric pH after single and multiple oral administration in humans.
Methods: The plasma concentrations of YH4808 and intragastric pH profiles obtained from healthy subjects who received a single (30-800 mg) or multiple (100-400 mg) oral doses or their matching placebos (intragastric pH only) were pooled and a pharmacokinetic and pharmacodynamic model was developed simultaneously using the first-order conditional estimation with interaction (FOCE-I) method implemented in NONMEM version 7.3 (ICON Development Solutions, Ellicott City, MD, USA). The effects of the covariates (i.e., age, body weight and height) were also evaluated and tested. The final model was qualified based on the precision of parameter estimates, diagnostic plots and visual predictive check plots.
Results: We pooled 1627 plasma concentrations and 1846 intragastric pH points from 80 subjects (56 and 24 for single and multiple dose studies, respectively), aged 20-41 years and weighing 53.5-87.2 kg. A two-compartment pharmacokinetic model with lagged first-order absorption model and a sigmoid maximum effect model linked with an effect compartment best described the observed YH4808 plasma concentrations and intragastric pH profiles over 24-hour period after YH4808 dosing, respectively. To address changes in intragastric pH over time affecting the plasma concentration of YH4808, we introduced a feedback path such that increased intragastric pH decreases the relative bioavailability of YH4808. The intragastric pH profiles at baseline exhibited a circadian rhythm, which was well described by a four-harmonic function in the pharmacodynamic model. No covariates significantly affected the pharmacokinetic or pharmacodynamic parameters of YH4808. The typical values of Emax or the maximum effect and EC50 or the drug concentration that produces half of Emax were 6.9 (95% confidence interval (CI): 6.6-7.3) and 206.4 ng/mL (95% CI: 201.3-211.5 ng/mL), respectively. The interindividual variability of Emax and EC50 was 19.6% (95% CI: 16.2-23.1%) and 3.5% (95% CI: -3.0-10.1%), respectively.
Conclusions: We developed a pharmacokinetic and pharmacodynamic model that adequately described quantitative mutual relationships between the plasma concentrations of YH4808 and the time course of intragastric pH after single and multiple oral administrations in humans. Our analysis provides mechanistic insight into the relationship between the exposure to YH4808 and intragastric pH, which will allow for devising optimal dosing regimens for YH4808 in future clinical studies.
References:
[1] Yi S et al. Aliment Pharmacol Ther, 46(3): 337-346, 2017.
[2] Lee HA et al. Eur J Pharm Sci, 130:1-10, 2019.
Reference: PAGE 28 (2019) Abstr 9070 [www.page-meeting.org/?abstract=9070]
Poster: Methodology - New Modelling Approaches