Integration of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Tegoprazan and Its Metabolite: Application for Predicting Food Effect and Intragastric pH Alterations

Abstract

A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for tegoprazan and its major metabolite M1 was developed to predict PK and PD profiles under various scenarios. The PBPK model for tegoprazan and M1 was developed and predicted using the SimCYP® simulator and verified using clinical study data obtained after a single administration of tegoprazan. The established PBPK/PD model was used to predict PK profiles after repeated administrations of tegoprazan, postprandial PK profiles, and intragastric pH changes. The predicted tegoprazan and M1 concentration–time profiles fit the observed profiles well. The arithmetic mean ratios (95% confidence intervals) of the predicted to observed values for the area under the curve (AUC0–24 h), maximum plasma drug concentration (Cmax), and clearance (CL) for tegoprazan and M1 were within a 30% interval. Delayed time of maximum concentration (Tmax) and decreased Cmax were predicted in the postprandial PK profiles compared with the fasted state. This PBPK/PD model may be used to predict PK profiles after repeated tegoprazan administrations and to predict differences in physiological factors in the gastrointestinal tract or changes in gastric acid pH after tegoprazan administration.

Development of a Physiologically Based Pharmacokinetic Model for Tegoprazan: Application for the Prediction of Drug–Drug Interactions with CYP3A4 Perpetrators

“…The major metabolic pathway of tegoprazan is in the liver, and the kidney excretes a negligible amount [ 2 , 3 ]. Both in vitro and clinical results have elucidated that tegoprazan is a potential substrate of cytochrome P450 (CYP) 3A4 [ 2 , 3 , 4 , 5 , 6 ]. An in vitro study reported that ketoconazole, a strong inhibitor of CYP3A4, significantly inhibited the metabolism of tegoprazan in human liver microsomes [ 5 ].…”

“…When tegoprazan was coadministered with another potent inhibitor of CYP3A34 (clarithromycin) in a clinical study, the maximum concentration ( C max ) and area under the concentration curve ( AUC ) during one dosing interval in the steady state of tegoprazan were increased 2.2-fold and 2.7-fold, respectively, compared with the administration of tegoprazan alone [ 6 ]. In addition to CYP3A4, it has been reported that tegoprazan is metabolized partly by CYP2C19 [ 2 , 3 , 4 ]. In the presence of recombinant CYP3A4 and CYP2C19, the intrinsic clearance of tegoprazan was 0.86 and 0.61 µL/min/pmol protein, respectively [ 4 ].…”

“…In addition to CYP3A4, it has been reported that tegoprazan is metabolized partly by CYP2C19 [ 2 , 3 , 4 ]. In the presence of recombinant CYP3A4 and CYP2C19, the intrinsic clearance of tegoprazan was 0.86 and 0.61 µL/min/pmol protein, respectively [ 4 ]. The metabolite M1 (desmethyl tegoprazan) is the major metabolite of tegoprazan, which equals 6.8% of the total administered tegoprazan dose.…”

“…In the literature, two physiologically based pharmacokinetic (PBPK) models for tegoprazan have been reported, developed by Yoon et al [ 5 ] and Jeong et al [ 4 ]. Both studies used the commercially available software Simcyp Simulator to build the PBPK model and generate the PK simulations.…”

“…However, the PBPK model for the metabolite M1 and the effect of food on the PK of tegoprazan (and, consequently, the PK of its metabolite) was not considered [ 5 ]. In the study by Jeong et al [ 4 ], an improved PBPK model for tegoprazan and M1 to overcome the limitation of the previous model was reported. However, in this study, the plasma concentration–time profiles of tegoprazan and M1 from only one clinical study (subjects received a single dose of tegoprazan 100mg) were used for the model’s development.…”