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Effects of pirenzepine on vonoprazan-induced gastric acid inhibition and hypergastrinemia.
Suzuki, T, Higuchi, T, Kagami, T, Uotani, T, Yamade, M, Tani, S, Hamaya, Y, Iwaizumi, M, Osawa, S, Sugimoto, K, et al
European journal of clinical pharmacology. 2021;(7):971-978
Abstract
BACKGROUND Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. METHODS Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75 mg alone, vonoprazan 10 mg alone, and vonoprazan 10 mg plus pirenzepine 75 mg administered in a randomized crossover fashion. RESULTS Median pH 4 holding time ratios (range) achieved with pirenzepine 75 mg, vonoprazan 10 mg, and vonoprazan 10 mg plus pirenzepine 75 mg were 6.9% (2.4-32.8%), 88.4% (54.6-100%), and 84.2% (40.3-100%), respectively. Respective serum gastrin levels were 79 (75-210) pg/ml, 310 (110-870) pg/ml, and 170 (140-930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200 pg/ml) induced by vonoprazan 10 mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180 pg/ml (P = 0.028). CONCLUSION Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.
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Pharmacodynamics and pharmacokinetics of DWP14012 (fexuprazan) in healthy subjects with different ethnicities.
Hwang, JG, Jeon, I, Park, SA, Lee, A, Yu, KS, Jang, IJ, Lee, S
Alimentary pharmacology & therapeutics. 2020;(11-12):1648-1657
Abstract
BACKGROUND DWP14012 (fexuprazan), a novel potassium-competitive acid blocker, is under development for the treatment of acid-related disorders. AIMS To compare the pharmacodynamics (PDs), pharmacokinetics (PKs) and safety of DWP14012 among healthy subjects of Korean, Caucasian and Japanese descent. METHODS A randomised, double-blind, placebo-controlled, single- and multiple-dose study was conducted. Ten subjects in each dose group (40, 60 or 80 mg for Koreans; 40 or 80 mg for Caucasians; 20, 40 or 80 mg for Japanese) were randomly assigned to DWP14012 or a placebo. Twenty-four-hour intragastric pH measurements and serial blood samples were collected for PK/PD evaluation. The PK/PD parameters were compared between each ethnicity. RESULTS The extent of gastric acid suppression was similar among the ethnicities; the mean percentages of time that the intragastric pH was above 4 after multiple doses of 40 mg in the Korean, Caucasian and Japanese subjects were 64.3%, 62.8% and 70.3%, respectively, and the corresponding values for the 80 mg dose were 94.8%, 90.6% and 90.6% respectively. The changes in serum gastrin were not clinically significant between all three ethnicities. The systemic exposure of DWP14012 was similar between the three ethnicities after the 40 mg doses but slightly lower in Caucasian and Japanese subjects after the 80 mg doses. Gastric acid suppression by DWP14012 showed a clear exposure-response relationship in the three ethnicities. CONCLUSIONS Gastric acid suppression by DWP14012 was similar among the Korean, Caucasian and Japanese subjects in this study, and the PK, PK-PD relationships and safety were also similar among the three ethnicities. DWP14012 could be used without consideration of ethnicity.
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Randomised trial of acid inhibition by vonoprazan 10/20 mg once daily vs rabeprazole 10/20 mg twice daily in healthy Japanese volunteers (SAMURAI pH study).
Takeuchi, T, Furuta, T, Fujiwara, Y, Sugimoto, M, Kasugai, K, Kusano, M, Okada, H, Suzuki, T, Higuchi, T, Kagami, T, et al
Alimentary pharmacology & therapeutics. 2020;(5):534-543
Abstract
BACKGROUND Vonoprazan (V), a potassium-competitive acid blocker, has a more durable acid-inhibitory effect as compared with standard-dose proton pump inhibitors (PPIs) but has not been compared with 2-4 times higher daily PPI doses administered in two divided doses. AIMS To evaluate the acid-inhibitory effect of V 10/20 mg once-daily (OD; V10/V20) vs rabeprazole (R) 10/20 mg twice-daily (BID; R20/R40) in healthy Japanese volunteers. METHODS This multicentre, randomised, open-label, two-period, crossover study compared V10 or V20 vs R20, or V20 vs R40 using three cohorts of 10 healthy Japanese adults. Within each cohort, subjects were randomised to receive V or R for 7 days and, following a washout period ≥7 days, the other treatment for 7 days. On day 6 of each period, 24-hours multichannel gastric impedance-pH monitoring was performed. Percent times pH ≥ 3, ≥4 and ≥5 (pH 3, 4 and 5 holding time ratios [HTRs]) in 24 hours were evaluated as primary pharmacodynamic endpoints. RESULTS Acid-inhibitory effect (24-hours pH 3 HTR) of V20 was greater than those of R20 (91.0% vs 65.3%; P = .0049) and R40 (98.5% vs 85.9%; P = .0073). Similar results were obtained for 24-hours pH 4 and 5 HTRs. V20 also achieved greater nocturnal pH 4 (91.5% vs 73.2%; P = .0319) and 5 HTRs (78.8% vs 62.2%; P = .0325) as compared with R40. One subject (20%) developed diarrhoea while receiving R40 which was considered treatment-related. CONCLUSIONS Compared with 2-4 times the standard daily dose of R, V20 exerts a more potent and durable acid-inhibitory effect. Trial identifier: UMIN000022198 (www.umin.ac.jp/ctr/index.htm).
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Two placebo-controlled crossover studies in healthy subjects to evaluate gastric acid neutralization by an alginate-antacid formulation (Gaviscon Double Action).
Wilkinson, J, Abd-Elaziz, K, den Daas, I, Wemer, J, van Haastert, M, Hodgkinson, V, Foster, M, Coyle, C
Drug development and industrial pharmacy. 2019;(3):430-438
Abstract
OBJECTIVE To investigate the intragastric acid neutralization activity of a combined alginate-antacid formulation. SIGNIFICANCE Published studies have investigated the reflux-suppressing alginate component of Gaviscon Double Action (Gaviscon DA; RB, UK) but intragastric acid neutralization activity of the antacid component has not been evaluated in vivo. METHODS Intragastric pH monitoring, using a custom-made 10-electrode catheter, was evaluated in a two-part exploratory study in healthy subjects; Part I (n = 6) tested suitability of the catheter using antacid tablets (Rennie; Bayer, Germany); Part II (n = 12) evaluated gastric acid neutralization activity of Gaviscon DA liquid (20 ml) versus placebo in fasted subjects using a randomized, open-label, crossover design. The primary endpoint was the percentage of time that intragastric pH ≥4 was measured during 30 min post-treatment. A confirmatory study of identical design was subsequently conducted (n = 20). RESULTS Monitoring pH using the multielectrode catheter was a viable approach, directly detecting changes in intragastric pH following a single dose of antacid tablets. In the exploratory study, the percentage of time that pH ≥4 during 30 minutes post-treatment was 46.8% with Gaviscon DA liquid versus 4.7% with placebo (p = 0.0004). These findings were supported by the confirmatory study, where pH ≥4 was recorded 50.8% of the time with Gaviscon DA versus 3.5% with placebo (p = 0.0051). In this study, Gaviscon DA was safe and well tolerated. CONCLUSIONS These studies demonstrate the effective acid neutralizing capacity of Gaviscon DA versus placebo in healthy, fasted subjects. This adds to the evidence base for the combination of alginates and antacids.
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Food, Acid Supplementation and Drug Absorption - a Complicated Gastric Mix: a Randomized Control Trial.
Surofchy, DD, Frassetto, LA, Benet, LZ
Pharmaceutical research. 2019;(11):155
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Abstract
PURPOSE The purpose of this study was to determine the impact of food on gastric pH and the ability of over the counter betaine hydrochloride (BHCl) acid to reacidify gastric pH after food-induced elevations in gastric pH. METHODS This open-label cross over clinical study (NCT02758015) included 9 subjects who were randomly assigned to one of 16 possible, 4-period cross-over sequences to determine the impact and relationship of food and gastric pH with acid supplementation. Subjects were administered various doses (1500 mg, 3000 mg and 4500 mg) of betaine hydrochloride (BHCl) to determine the ability of acid supplementation to reacidify gastric pH after the elevation of gastric pH caused by the ingestion of food. RESULTS Following the administration of food and the resulting elevation in gastric pH, time to return to baseline gastric pH levels without acid supplementation was 49.7 ± 14.0 min. Administering 4500 mg of BHCl acid in capsules was able to reacidify gastric pH levels back to baseline following the administration of food in approximately 17.3 ± 5.9 min. AUCpH of each treatment were similar and not statistically different. Mean max pH following the administration of food was 3.20 ± 0.55. CONCLUSION The ability of food to elevate and maintain gastric pH levels in the presence of acid supplementation was made evident throughout the study. A 4500 mg dose of BHCl was required to reacidify gastric pH after the administration of food. This study details the difficulty faced by clinicians in dosing a poorly soluble, weakly basic drug to patients receiving acid reducing agents where administration with food is recommended to avoid gastric side effects. TRIAL REGISTRATION https://clinicaltrials.gov/ct2/show/NCT02758015.
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Randomised clinical trial: safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of tegoprazan (CJ-12420), a novel potassium-competitive acid blocker, in healthy male subjects.
Han, S, Choi, HY, Kim, YH, Nam, JY, Kim, B, Song, GS, Lim, HS, Bae, KS
Alimentary pharmacology & therapeutics. 2019;(7):751-759
Abstract
BACKGROUND Tegoprazan (CJ-12420) is a potassium-competitive acid blocker (P-CAB) with therapeutic potential for gastro-oesophageal reflux disease (GERD) by reversibly suppressing gastric H+ /K+ -ATPase. AIMS To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of tegoprazan METHODS A phase I, randomised, double-blind and placebo-controlled clinical trial was conducted in 56 healthy male subjects without Helicobacter pylori infection. In the single ascending dose study, 50, 100, 200 and 400 mg tegoprazan were administered to 32 subjects. In the multiple ascending dose study, 100 and 200 mg tegoprazan were administered every 24 hours to each of the eight subjects for 7 days. In the comparative pharmacodynamics study, 40 mg esomeprazole was administered to eight subjects every 24 hours for 7 days. The assessment included safety, tolerability, pharmacodynamics through monitoring of 24-hour gastric pH and pharmacokinetics of tegoprazan in plasma and urine. RESULTS Tegoprazan was generally well tolerated. Most adverse events reported in the study were mild in intensity and resolved without any sequelae. Exposure to tegoprazan increased in a dose-proportional manner. Multiple dosing with tegoprazan showed no accumulation in plasma on day 7. The pharmacodynamic analysis revealed that tegoprazan showed rapid, dose-dependent gastric acid suppression. CONCLUSIONS Tegoprazan was well tolerated and showed rapid and potent gastric acid suppression. This supports the further development of tegoprazan as a treatment for acid-related disorders.
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Effect of food on the pharmacokinetics of YH4808, a potassium-competitive acid blocker, after single- and multiple-oral dosing in healthy subjects.
Kim, E, Kim, A, Yi, S, Kim, YK, Jang, SB, Byun, HM, Yoon, SH, Cho, JY, Jang, IJ, Yu, KS, et al
European journal of clinical pharmacology. 2018;(10):1261-1272
Abstract
PURPOSE YH4808 is a potassium-competitive acid blocker, developed for the treatment of acid-related disorders. Two clinical studies in healthy male subjects were conducted to evaluate the effect of food on the pharmacokinetics of YH4808. METHODS The first study, a randomized, three-treatment, three-period, crossover study, compared pharmacokinetics of YH4808 (300 mg) after a single dose at fed state with a standard or a high-fat meal to those at fasted state. The second study, a randomized, two-treatment, two-period, crossover study, investigated pharmacokinetics at fasted or fed state with a standard meal after twice daily dose of YH4808 (100 mg) for 7 days. Bloods for pharmacokinetic evaluation were sampled up to 48 h post-dose and 24 h post-dose at steady state, respectively. The pharmacokinetic parameters were estimated by non-compartmental method. RESULTS After single dosing, the geometric means of maximum plasma concentration increased by 1.2 and 2.1 times in the fed states with a standard meal and a high-fat meal, respectively, of that in fasted state. Corresponding values of area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time point increased by 1.8 and 2.8 times, respectively. After multiple dosing, the geometric mean for 24-h AUC at steady state slightly increased in fed state by 1.1 times of that in fasted state. CONCLUSIONS As fat content of the food increased, the systemic exposure of YH4808 after single dosing increased. However, systemic exposures at steady state after multiple dosing between fasted and fed states were similar. TRIAL REGISTRATION ClinicalTrials.gov registry no.: NCT01520012.
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A dark brown roast coffee blend is less effective at stimulating gastric acid secretion in healthy volunteers compared to a medium roast market blend.
Rubach, M, Lang, R, Bytof, G, Stiebitz, H, Lantz, I, Hofmann, T, Somoza, V
Molecular nutrition & food research. 2014;(6):1370-3
Abstract
Coffee consumption sometimes is associated with symptoms of stomach discomfort. This work aimed to elucidate whether two coffee beverages, containing similar amounts of caffeine, but differing in their concentrations of (β) N-alkanoyl-5-hydroxytryptamides (C5HTs), chlorogenic acids (CGAs), trigonelline, and N-methylpyridinium (N-MP) have different effects on gastric acid secretion in healthy volunteers. The intragastric pH after administration of bicarbonate with/without 200 mL of a coffee beverage prepared from a market blend or dark roast blend was analyzed in nine healthy volunteers. Coffee beverages were analyzed for their contents of C5HT, N-MP, trigonelline, CGAs, and caffeine using HPLC-DAD and HPLC-MS/MS. Chemical analysis revealed higher concentrations of N-MP for the dark brown blend (87 mg/L) compared to the market blend coffee (29 mg/L), whereas concentrations of C5HT (0.012 versus 0.343 mg/L), CGAs (323 versus 1126 mg/L), and trigonelline (119 versus 343 mg/L) were lower, and caffeine concentrations were similar (607 versus 674 mg/mL). Gastric acid secretion was less effectively stimulated after administration of the dark roast blend coffee compared to the market blend. Future studies are warranted to verify whether a high ratio of N-MP to C5HT and CGAs is beneficial for reducing coffee-associated gastric acid secretion.
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Effect of gastric acid suppression with pantoprazole on the efficacy of sevelamer hydrochloride as a phosphate binder in haemodialysis patients: a pilot study.
Lai, B, Cervelli, MJ
Nephrology (Carlton, Vic.). 2012;(4):402-6
Abstract
Sevelamer hydrochloride (HCL) is thought to require an appropriately acidic environment in order to bind gastrointestinal phosphate. Changes in gastric acidity with acid suppressants may therefore alter the efficacy of sevelamer HCL. Given the widespread use of acid suppression therapy in chronic kidney disease patients, there is potential for a common significant drug interaction to occur. This pilot study evaluated the in vivo effect of gastric acid suppression with pantoprazole on the efficacy of sevelamer HCL as a phosphate binder in maintenance haemodialysis patients. The study protocol was a cross-over, double-blinded, randomized, placebo-controlled trial in 10 haemodialysis patients randomly assigned to pantoprazole 40 mg daily or placebo for two consecutive 6-week periods. Serum phosphate was not significantly altered during pantoprazole compared with placebo treatment (1.61 ± 0.45 mmol/L vs 1.76 ± 0.42 mmol/L, P = 0.204). There were no differences in serum calcium, parathyroid hormone and bicarbonate. This pilot study demonstrates preliminary in vivo evidence for no effect of gastric acid suppression on the effectiveness of sevelamer HCL. Our results are limited by small sample size and therefore, larger experimental studies should be conducted. Although our study did not find a significant drug interaction, given the high prevalence of acid suppressant use in dialysis patients, physicians should be aware of the potential influence of acid suppression on the efficacy of phosphate binders and regularly assess the clinical need for acid suppression therapy.
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The effect of once daily omeprazole and succinic acid (VECAM) vs once daily omeprazole on 24-h intragastric pH.
Chowers, Y, Atarot, T, Pratha, VS, Fass, R
Neurogastroenterology and motility. 2012;(5):426-31, e208-9
Abstract
BACKGROUND Parietal cell H(+)/K(+) ATPase activation is essential for optimal proton pump inhibitor (PPI) activity. Succinic acid (SA) was shown to induce gastric acid secretion. VECAM is a combination of omeprazole (OMP) and SA. To compare the effect of once daily bedtime dosing of VECAM 40 and VECAM 20 without food vs OMP 20 mg administered before breakfast on gastric acidity. METHODS Open label, randomized, crossover study enrolling 36 healthy subjects comparing the study treatments at steady state for 24 h intragastric pH monitoring. KEY RESULTS The median percent time intragastric pH > 4 demonstrated that VECAM 40 was superior to VECAM 20 (65.7%vs 49.1%P < 0.0001) and OMP 20 mg (65.7%vs 47.6%P = 0.005) during 24 h. VECAM 40 was superior to VECAM 20 (52.8%vs 38.8%P = 0.0079) and OMP 20 mg (52.8%vs 27.2%P < 0.0001), and VECAM 20 was superior to OMP 20 mg (38.8 vs 27.2 P = 0.0069) during the nighttime. VECAM 20 and OMP 20 mg were comparable during 24 h. CONCLUSIONS & INFERENCES VECAM 40 and VECAM 20 were significantly better in maintaining intragastric pH > 4 during the nighttime than OMP 20 mg. Succinic acid eliminates the need for a subsequent meal for intragastric pH control by VECAM.