Effect of meal timing on pharmacokinetics and pharmacodynamics of tegoprazan in healthy male volunteers

Abstract

Tegoprazan, a novel potassium‐competitive acid blocker, is used to treat acid‐related diseases. However, there is no information on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the marketed dosage of tegoprazan under various meal timings in a fed and fasted state. The study aimed to assess the effect of meal timing on PKs and PDs of tegoprazan 50 mg after a single administration in healthy male subjects. An open‐label, single‐dose, three‐treatment, three‐period crossover study was conducted. A total of 12 subjects were orally administered a single dose of tegoprazan 50 mg among various conditions: in a fasted state, at 30 min before or 30 min after a high‐fat meal. PK parameters were estimated by the noncompartmental method. Continuous 24‐h intragastric pH monitoring was done for PD analysis. The PKs and PDs of tegoprazan were compared among the various meal timings. Compared with the fasting condition, the PK profile of tegoprazan was similar when administered 30 min before a high‐fat meal; however, delayed absorption with similar systemic exposure was observed when administered 30 min after a high‐fat meal. The magnitude of acid suppression evaluated through the PD parameters increased when administered 30 min after a high‐fat meal compared with fasting the condition and when administered 30 min before a high‐fat meal. However, the increased difference in acid suppression was not clinically significant. Meal timing had no clinically significant effect on the PKs and PDs of tegoprazan 50 mg. Therefore, the marketed dosage of tegoprazan could be administered regardless of the meal timing. WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tegoprazan, a novel potassium‐competitive acid blocker, is used to treat acid‐related diseases. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated the effect of food on pharmacokinetics (PKs) and pharmacodynamics (PDs) of tegoprazan under various mealtime conditions. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study showed that delayed absorption of tegoprazan was observed at “after meal condition,” however, the amount of systemic exposure of “after meal condition” was similar to “fasting condition” and “before meal condition.” In addition, gastric acid suppression of tegoprazan was similar between fasting condition and before meal condition, whereas increased gastric acid suppression was observed at after meal condition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? In the actual clinical environment, patients take medicine under various fed conditions. This study evaluated the effect of food on PKs and PDs of tegoprazan in various clinical conditions, and provided the important information about meal timing when administering tegoprazan.

Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation

“…For example, the predicted exposure indices (i.e., C max and AUC) for single or repeated administration of tegoprazan were consistent with the results reported in previous clinical studies, satisfying the 2-fold criteria that is commonly used in IVIVE prediction [ 16 ]. The predicted range of time to reach C max was also comparable with the observed range in each trial [ 2 , 3 , 4 , 12 , 23 ]. In addition, the mean apparent clearance (i.e., AUC/dose) was predicted to be 17.5 L/h when tegoprazan was administered alone and decreased to 6.4 L/h by the co-administration of clarithromycin, which is similar to the results of the DDI study between tegoprazan and clarithromycin (17.7 L/h and 6.6 L/h, respectively) [ 4 ].…”

“…A possible reason for the decrease in C max after multiple doses is pH-dependent change in the absorption of tegoprazan, that is, the C max of tegoprazan might be reduced after multiple administrations due to augmented gastric pH caused by tegoprazan itself. In previous studies, when tegoprazan was administered with food, a decreased C max was observed with a delayed time to reach C max , which was explained by an increase in gastric pH as food dilutes the H + concentration in the stomach [ 12 , 28 ]. Because pH-dependent absorption was not reflected in the PBPK model, the difference between the observed and predicted C max might have occurred.…”

“…The PKs of tegoprazan has been investigated previously in various dosage ranges, and DDI with clarithromycin and food effect studies have also been performed [ 2 , 3 , 4 , 12 , 23 ]. However, there are still many aspects of PKs of tegoprazan unidentified mechanistically and clinically.…”

“…The commercially available software SimCYP simulator v19 (SimCYP Limited, Certara, Sheffield, UK) was used to build the PBPK model and to generate the PK simulations. The PBPK-model-predicted PK profiles and parameters of tegoprazan were compared with the observed PK profiles and parameters from previously conducted clinical studies [ 3 , 4 , 12 ] ( Supplementary Table S1 ). The specific model configuration related to absorption, distribution, and elimination is described below.…”

“…The established PBPK model was verified by applying the predicted values to the clinical PK data from various phase 1 studies conducted with healthy male adults ( Supplementary Table S2 ). Brief information about the clinical studies follows: study 1 (single-dose PK study), a single dose of tegoprazan 25 mg and 50 mg was orally administered; study 2 (food effect study), a single dose of tegoprazan 50 mg was orally administered in both fasted and fed states [ 12 ]; study 3 (bioequivalence study of two formulations), a single dose of two different formulations with tegoprazan 100 mg was orally administered [ 3 ]; study 4 (multiple-dose PK study), multiple doses of tegoprazan 50 mg and 100 mg were orally administered once daily for 7 days; study 5 (DDI study with clarithromycin), multiple doses of tegoprazan 200 mg were orally administered once daily with or without multiple doses of clarithromycin 500 mg twice daily for 5 days; and study 6 (DDI study with clarithromycin and amoxicillin), multiple doses of tegoprazan 100 mg were orally administered twice daily with or without multiple doses of clarithromycin/amoxicillin 500/1000 mg twice daily for 5 days or 7 days [ 4 ].…”