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Kim A, Shin D, Seo Y, Kang D, Min YW, Kim IH, Kim J. Phase I Study to Evaluate the Effect of Hepatic Impairment on Pharmacokinetics and Safety of Tegoprazan, a Potassium Competitive Acid Blocker. Adv Ther 2025; 42:1570-1581. [PMID: 39932678 DOI: 10.1007/s12325-025-03127-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Accepted: 01/24/2025] [Indexed: 02/28/2025]
Abstract
INTRODUCTION Tegoprazan is a potassium-competitive acid blocker, and its systemic exposure is presumably affected by hepatic clearance and bioavailability. This study aimed to investigate the effect of hepatic impairment (HI) on the safety and pharmacokinetics of tegoprazan and metabolite. METHODS An open-label, multicenter, parallel-group study was conducted in patients with mild (n = 8), moderate (n = 8) and severe (n = 1) HI according to the Child-Pugh classification as well as controls. Healthy subjects (n = 8) were matched to patients with the moderate category based on age, body mass index and sex. Blood and urine samples were obtained to evaluate the concentrations of tegoprazan and metabolite (M1) until 48 h after a single oral administration of 50 mg of tegoprazan. RESULTS The geometric mean ratio with a 90% confidence interval of maximum plasma concentration and area under the plasma concentration-time curve for tegoprazan in patients with impaired hepatic function compared to controls were 0.8228 (0.4997-1.3550) and 1.2264 (0.7447-2.0197) in the mild category, 1.0332 (0.6274-1.7015) and 1.7676 (1.0733-2.9109) in the moderate category, and 1.0699 (0.3713-3.0823) and 1.9567 (0.6792-5.6377) in the severe category. The half-life, apparent clearance, renal clearance, and fraction unbound to plasma protein were comparable across study groups. The plasma concentration of M1 increased and decreased faster in the normal group. Tegoprazan was generally well tolerated in patients with HI. CONCLUSIONS Systemic exposure to tegoprazan tended to be increased in subjects with HI. The difference between patients with mild HI and the controls was deemed not to require dose adjustment for tegoprazan. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT04494269 (31 Jul 2020).
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Affiliation(s)
- Anhye Kim
- Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea
- Department of Pharmacology, CHA University School of Medicine, Pocheon, Republic of Korea
| | - Dongseong Shin
- Department of Clinical Pharmacology and Therapeutics, Gachon University College of Medicine, Gil Medical Center, Incheon, Republic of Korea
| | - Youlim Seo
- Clinical Research Center, HK inno.N Corp, Seoul, Republic of Korea
| | - Deborah Kang
- Clinical Research Center, HK inno.N Corp, Seoul, Republic of Korea
| | - Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - In Hee Kim
- Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Jungryul Kim
- Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
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Cerf NT, Zerbetto de Palma G, Fedosova NU, Filomatori CV, Rossi RC, Faraj SE, Montes MR. How ligands modulate the gastric H,K-ATPase activity and its inhibition by tegoprazan. J Biol Chem 2024; 300:107986. [PMID: 39547508 PMCID: PMC11697777 DOI: 10.1016/j.jbc.2024.107986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/16/2024] [Accepted: 10/30/2024] [Indexed: 11/17/2024] Open
Abstract
The introduction of potassium-competitive acid blockers (P-CABs) has been a major innovation in gastric H,K-ATPase inhibition and many laboratories are actively engaged in the development of novel molecules within this class. This work investigates the interaction between H,K-ATPase and tegoprazan, a representative of the P-CABs group, in terms of K+ and H+ binding, through functional and structural analyses. First, by studying the H,K-ATPase activity, we found a model to describe the non-Michaelis-Menten kinetics through a "ping-pong" mechanism that explains a stoichiometry of 1 H+, 1 K+, and 1 ATP molecule, but also considering the influence of H+ on the ionization states of the protein. A kinetic evaluation of the inhibition of tegoprazan denotes the binding to two different intermediates states with apparent Kd (μM) 0.56 ± 0.04 and 2.70 ± 0.24 at pH 7.2. Molecular dynamics simulations revealed important changes in the interactions of tegoprazan with the transmembrane residues depending on whether the site contains K+ or not. This explains the decrease in affinity as a function of K+ concentration observed in the kinetic experiments. On the other hand, the structures predict that the protonation of tegoprazan is responsible for the change in its dihedral angle. The rotation of the benzimidazole ring allows the inhibitor to be positioned further into the luminal cavity, a situation compatible with the higher inhibition affinity of H,K-ATPase measured at low pH. Results presented herein will provide a basis for the rational design of novel P-CABs ligands.
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Affiliation(s)
- Nicole T Cerf
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | - Gerardo Zerbetto de Palma
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | | | - Claudia V Filomatori
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | - Rolando C Rossi
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | - Santiago E Faraj
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | - Mónica R Montes
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) - Universidad de Buenos Aires, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina.
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Lin X, Huang H, Liu Y, Zeng Y, Lu S, Xu X, Lin Y, Qiu F, Cai F, Pan J, Huang S, Lin S, Lin A, Lin Z, Huang X. Tegoprazan-Amoxicillin Dual Therapy for Helicobacter pylori Eradication: A Prospective, Randomized, Multicenter Study in Fujian, China. Helicobacter 2024; 29:e13151. [PMID: 39523458 DOI: 10.1111/hel.13151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/09/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Few studies have investigated the efficacy and safety of tegoprazan-amoxicillin (TA) dual therapy for Helicobacter pylori eradication. We aim to evaluate the effectiveness and safety of different dosages of TA dual therapy for H. pylori eradication. METHODS This prospective, randomized, open-label, multicenter study was conducted at four centers in Fujian, China. H. pylori-infective patients were randomized 1:1:1 to receive one of the following treatments: bismuth quadruple therapy (BQT, esomeprazole 20 mg twice daily + potassium bismuth citrate 240 mg twice daily + amoxicillin 1 g twice daily + clarithromycin 500 mg twice daily), tegoprazan-amoxicillin dual therapies (TA-qd, tegoprazan 50 mg once daily + amoxicillin 1 g thrice daily; TA-bid, tegoprazan 50 mg twice daily + amoxicillin 1 g thrice daily) for 14 days. The primary outcome was noninferiority in eradication rates of the different TA groups compared to the BQT group. Secondary outcomes encompassed an assessment of adverse reactions and clinical symptom relief. Additionally, exploratory outcomes were focused on the shifts in gut microbiota and a cost-effectiveness analysis. RESULTS A total of 321 patients were enrolled. The eradication rates in the BQT group, TA-qd group, and TA-bid group were 85.05% (91/107), 85.98% (92/107), and 85.98% (92/107) in the intention-to-treat analysis (ITT) (BQT vs. TA-qd, 95% CI -8.50% to 10.36%, noninferiority p = 0.012; BQT vs. TA-bid, 95% CI -8.50% to 10.36%, noninferiority p = 0.012); 91.00% (91/100), 91.09% (92/101), and 92.93% (92/99) in the modified intention-to-treat analysis (mITT) (BQT vs. TA-qd, 95% CI -7.81% to 7.98%, noninferiority p = 0.006; BQT vs. TA-bid, 95% CI -5.62% to 9.48%, noninferiority p < 0.001); 90.81% (89/98), 91.00% (91/100), and 93.81% (91/97) in the per-protocol analysis (PP) (BQT vs. TA-qd, 95% CI -7.83% to 8.19%, noninferiority p = 0.006; BQT vs. TA-bid, 95% CI 4.46% to 10.46%, noninferiority p < 0.001). The incidence of adverse reactions in the TA-qd and TA-bid groups was significantly lower than in the BQT group (13.33%, 14.56%, and 27.18%, respectively; p = 0.017). The complete remissions of clinical symptoms for BQT, TA-qd, and TA-bid were 36.89%, 65.71%, and 68.93%, respectively, had significant differences (p < 0.001). Two weeks of TA therapy altered gut microbiota diversity and composition, but that recovered 4 weeks after discontinuation. The cost-effectiveness ratios (CERs) for BQT, TA-qd, and TA-bid were 1.85 CNY, 2.08 CNY, and 3.69 CNY, respectively. CONCLUSION Both TA dual therapies provided satisfactory eradication rates of > 90% for eradicating H. pylori, fewer adverse reactions, and greater clinical symptom relief compared to BQT, with a mild, reversible impact on gut microbiota. In addition, the TA dual therapy with low doses of tegoprazan showed better cost-effectiveness. TRIAL REGISTRATION Chinese Clinical Trial Register and registration No.: ChiCTR2300071997.
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Affiliation(s)
- Xueyan Lin
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Huping Huang
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Yijuan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yanling Zeng
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Shiyun Lu
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Xuefeng Xu
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Yun Lin
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Feng Qiu
- Department of Gastroenterology, Fujian Provincial Geriatric Hospital, Fuzhou, China
| | - Fangfang Cai
- Department of Gastroenterology, Fujian Provincial Geriatric Hospital, Fuzhou, China
| | - Jie Pan
- Department of Gastroenterology, Pingtan Comprehensive Experimental Area Hospital, Fuzhou, China
| | - Shaozhong Huang
- Department of Gastroenterology, Pingtan Comprehensive Experimental Area Hospital, Fuzhou, China
| | - Shaowei Lin
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Aiping Lin
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Zhihui Lin
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
| | - Xueping Huang
- Department of Gastroenterology, The Shengli Clinical Medical College, Fujian Medical University, Fuzhou, China
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, China
- Department of Gastroenterology, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China
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Scarpignato C, Hunt RH. Potassium-competitive Acid Blockers: Current Clinical Use and Future Developments. Curr Gastroenterol Rep 2024; 26:273-293. [PMID: 39145848 PMCID: PMC11401795 DOI: 10.1007/s11894-024-00939-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2024] [Indexed: 08/16/2024]
Abstract
PURPOSE OF THE REVIEW Acid suppression with proton pump inhibitors (PPIs) represents the standard of care in the treatment of acid-related diseases. However, despite their effectiveness, PPIs display some intrinsic limitations, which underlie the unmet clinical needs that have been identified over the past decades. The aims of this review are to summarize the current status and future development of the new class of antisecretory drugs (potassium-competitive acid blockers, P-CABs) that have recently been introduced into medical practice. RECENT FINDINGS Over the past decades, clinical needs unmet by the current acid suppressants have been recognized, especially in the management of patients with GERD, Helicobacter pylori infection and NSAID-related peptic ulcer. The failure to address these needs is mainly due to their inability to achieve a consistent acid suppression in all patients and, particularly, to control nighttime acidity. It was then realized that an extended duration of acid suppression would exert additional benefits. The available data with P-CABs show that they are able to address these unmet clinical needs. Four different P-CABs (vonoprazan, tegoprazan, fexuprazan and keverprazan) are currently available. However, only two of them are approved outside Asia. Vonoprazan is available in North, Central and South America while tegoprazan is marketed only in Latin American countries. Two other compounds (namely linazapran glurate and zestaprazan) are presently under clinical development. While clinical trials on GERD have been performed with all P-CABs, only vonoprazan and tegoprazan have been investigated as components of Helicobacter pylori eradication regimens. The available data show that-in the above two clinical indications-P-CABs provide similar or better efficacy in comparison with PPIs. Their safety in the short-term overlaps that of PPIs, but data from long-term treatment are needed.
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Affiliation(s)
- Carmelo Scarpignato
- Department of Medicine & Surgery, University of Parma, Parma, Italy.
- Department of Health Sciences, United Campus of Malta, Msida, Malta.
- Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, Hong Kong.
- Faculty of Medicine, University of Nantes, Nantes, France.
| | - Richard H Hunt
- Department of Medicine, Division of Gastroenterology and Farncombe Family Digestive, Health Research Institute, McMaster University, Hamilton, ON, Canada
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Kim GH, Lee HL. Efficacy of fexuprazan compared with rebamipide in Korean patients with gastritis: A matching-adjusted indirect comparison. World J Clin Cases 2024; 12:3890-3897. [PMID: 38994306 PMCID: PMC11235425 DOI: 10.12998/wjcc.v12.i19.3890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/03/2024] [Accepted: 05/22/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND Gastritis is one of the most frequently diagnosed diseases requiring medical treatment in South Korea. Fexuprazan, a novel potassium-competitive acid blocker, has been approved for treating gastritis and erosive esophagitis. Meanwhile, rebamipide is the most commonly used mucoprotective agent for acute and chronic gastritis in real-world settings in South Korea. However, there have been no studies comparing the efficacy of these two drugs yet. AIM To compare the efficacy of fexuprazan with that of rebamipide for acute and chronic gastritis. METHODS This was a matching-adjusted indirect comparison. Individual patient data from a phase III study of fexuprazan (10 mg BID) were compared with cumulative data from two matching studies of rebamipide (100 mg TID). Erosion improvement and healing rates were compared between two weeks of fexurapan, two weeks of rebamipide, and four weeks of rebamipide. The two main outcome variables were presented as percentages, and the risk differences (RD) and 95% confidence intervals (CI) were calculated for the relative treatment effects. RESULTS In the primary analysis, the erosion improvement and healing rates after a two-week treatment with fexuprazan were 64.5% and 53.2%, respectively, while a two-week treatment with rebamipide resulted in erosion improvement and healing rates of 43.6% (RD: 21.0%; 95%CI: 9.6-32.3; P < 0.01) and 35.6% (RD: 17.6%; 95%CI: 6.1-29.2; P = 0.003), respectively. In the additional analysis, the erosion improvement and healing rates for the two-week fexuprazan treatment (64.2% and 51.2%, respectively) were similar to those obtained during a four-week treatment with rebamipide (60.6%; RD: 3.6%; 95%CI: -9.8, 17.0; P = 0.600 and 53.5%; RD: -2.3%; 95%CI: -16.1, 11.5; P = 0.744, respectively). CONCLUSION The two-week fexuprazan treatment was superior to the two-week rebamipide treatment and similar to the four-week rebamipide treatment for patients with gastritis.
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Affiliation(s)
- Gwang Ha Kim
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Hang Lak Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul 04763, South Korea
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Kim HS, Choi YK, Oh M, Cho YS, Ghim JL. Enhancing drug administration flexibility: evaluation of pharmacokinetic properties of tegoprazan orally disintegrating tablet (ODT) administered via nasogastric tube or oral dosing. Transl Clin Pharmacol 2024; 32:98-106. [PMID: 38974342 PMCID: PMC11224899 DOI: 10.12793/tcp.2024.32.e9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 05/26/2024] [Accepted: 06/13/2024] [Indexed: 07/09/2024] Open
Abstract
Tegoprazan orally disintegrating tablet (ODT) formulation is a novel formulation to improve a convenience in comparison to taking the conventional tablet of tegoprazan, a potassium-competitive acid blocker. The purpose of this study was to evaluate the pharmacokinetic and safety profiles of tegoprazan ODT when administered via two routes: nasogastric tube or oral dosing. This study is expected to expand the administration route of tegoprazan ODT. The study was conducted in an open-label, randomized, single-dose, two-way crossover design with a 1-week washout period. Healthy subjects aged 19 to 45 years were administered 50 mg of tegoprazan ODT orally or dissolved in water via nasogastric tube. Tegoprazan, the active ingredient, was quantified using a ultra-high performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS), and pharmacokinetic parameters were determined through non-compartmental analysis. Safety was monitored throughout the study. A total of 48 subjects, successfully completed the trial. The geometric mean ratios for log-transformed Cmax and AUCt, representing the ratio of nasogastric tube group to oral dosing group, along with 90% confidence intervals, were 1.1087 (1.0243-1.2000) and 1.0023 (0.9620-1.0442), respectively. All adverse events were unrelated to tegoprazan and mild in intensity. The pharmacokinetic profiles of tegoprazan ODT were equivalent between the nasogastric tube and oral administration. Considering the demonstrated linear pharmacokinetics and concentration-dependent pharmacodynamics of tegoprazan, the administration via nasogastric tube is expected to yield effects equivalent to those of oral administration. This approach offers a viable alternative, especially beneficial for patients with oral intake difficulties.
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Affiliation(s)
- Ho-Sook Kim
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan 47392, Korea
| | - Young-Kyung Choi
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan 47392, Korea
| | - Minkyung Oh
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan 47392, Korea
| | - Yong-Soon Cho
- Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan 47392, Korea
| | - Jong-Lyul Ghim
- Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan 47392, Korea
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Zheng H, Yuan S, Liu J. Efficacy and safety of tegoprazan in the treatment of gastroesophageal reflux disease: A protocol for meta-analysis and systematic review. PLoS One 2024; 19:e0302450. [PMID: 38696509 PMCID: PMC11065240 DOI: 10.1371/journal.pone.0302450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/31/2024] [Indexed: 05/04/2024] Open
Abstract
OBJECTIVE The incidence of gastroesophageal reflux disease (GERD) is increasing year by year, the clinical manifestations are complex and diverse, and the adverse effects of long-term use of proton pump inhibitors and gastrointestinal motility drugs have been of great concern in recent years. The effectiveness of tegoprazan in the treatment of GERD is still controversial. This protocol describes a systematic review and meta-analysis to evaluate the efficacy and safety of tegoprazan in the treatment of gastroesophageal reflux disease. METHODS PubMed, Embase, Cochrane Library and Web of Science will be searched from the database inception to 1 March 2023. All randomized controlled trials related to tegoprazan for GERD will be included. Extracted data will include publication details, basic information, demographic data, intervention details and patient outcomes. The primary outcome will be complete resolution of major symptoms, complete resolution of heartburn, proportion of heartburn-free days, chronic cough, hoarseness, and adverse events. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing risk of bias. Article selection, data extraction and risk of bias assessment will be performed in duplicate by two independent reviewers. If the meta-analysis is precluded, we will conduct a descriptive synthesis using a best-evidence synthesis approach. DISCUSSION The results of this study will provide reliable evidence to evaluate the efficacy and safety of tegoprazan in the treatment of GERD and help patients, physicians and clinical investigators choose the most appropriate treatment.
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Affiliation(s)
- Hanxue Zheng
- Department of Otorhinolaryngology Head and Neck Surgery, Deyang People’s Hospital, Deyang Hospital Affiliated to Chengdu University of Traditional Chinese Medicine, Deyang, Sichuan, China
| | - Shunqi Yuan
- Department of Otolaryngology Head and Neck Surgery, Longquanyi Hospital of West China Hospital of Sichuan University (The First People’s Hospital of Longquanyi District of Chengdu), Chengdu, China
| | - Jianmin Liu
- Thyroid -ENT Head and Neck Surgery Department, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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Zou S, Ouyang M, Cheng Q, Shi X, Sun M. Acid-suppressive drugs: A systematic review and network meta-analysis of their nocturnal acid-inhibitory effect. Pharmacotherapy 2024; 44:171-183. [PMID: 38049205 DOI: 10.1002/phar.2899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 11/02/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023]
Abstract
BACKGROUND AND AIMS Acid-suppressive drugs (ASDs) are widely used in many gastric acid-associated diseases. Nocturnal acid breakthrough has been a common problem of many ASDs, such as proton-pump inhibitors (PPIs) and H2 -receptor antagonists (H2RAs). Potassium-competitive acid blockers (P-CABs) are expected to solve this continuing conundrum. This article examined major ASDs and compared them with placebo in terms of nocturnal acid-inhibitory effects, using a network meta-analysis of randomized controlled trials (RCTs). METHODS To compare the effectiveness of major ASDs, a Bayesian network meta-analysis (NMA) was applied to process data extracted from RCTs. The plausible ranking for each regimen and some subgroups were assessed by surface under the cumulative ranking curves (SUCRA). RESULTS Fifty-five RCTs were conducted with 2015 participants. In terms of nocturnal acid-inhibitory effects, the overall results showed that tegoprazan (SUCRA 91.8%) and vonoprazan (SUCRA 91.0%) had the best performance, followed by new PPIs (including tenatoprazole and ilaprazole) (SUCRA 76.6%), additional H2RAs once at bedtime (AHB) (SUCRA 61.3%), isomer PPIs (including esomeprazole and dexlansoprazole) (SUCRA 38.6%), revaprazan (SUCRA 34.7%), traditional PPIs (including omeprazole, rabeprazole, pantoprazole, lansoprazole) (SUCRA 32.6%), H2RAs (SUCRA 23.1%), and placebo (SUCRA 0.3%). In some subgroups, the nocturnal acid-inhibitory effect of vonoprazan or tegoprazan was better than most of the other regimens, even new PPIs and AHB. CONCLUSIONS This is the first study to compare the effect of ASDs on inhibiting nocturnal acid breakthrough. Overall, in terms of nocturnal acid-inhibitory effect, vonoprazan and tegoprazan had an advantage against other regimens including H2RAs, isomer PPIs, traditional PPIs, AHB, and new PPIs. Even in some subgroups, such as language classification (English), types of study design (crossover-RCT), age (≤40 years), BMI (18.5-24.9 kg/m2 ), continent (Asia and North America), disease status (health), the duration of therapy (2 weeks), and time of administration (at daytime or at night-time), the nocturnal acid-inhibitory effect of vonoprazan or tegoprazan were better than most regimens, even AHB and new PPIs.
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Affiliation(s)
- Shupeng Zou
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mengling Ouyang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Qian Cheng
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xuan Shi
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Minghui Sun
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Kim GH, Choi MG, Kim JI, Lee ST, Chun HJ, Lee KL, Choi SC, Jang JY, Lee YC, Kim JG, Kim KB, Shim KN, Sohn CI, Kim SK, Kim SG, Jang JS, Kim N, Jung HY, Park H, Huh KC, Lee KJ, Hong SJ, Baek S, Han JJ, Lee OY. Efficacy and Safety of Fexuprazan in Patients with Acute or Chronic Gastritis. Gut Liver 2023; 17:884-893. [PMID: 36789577 PMCID: PMC10651377 DOI: 10.5009/gnl220457] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/12/2022] [Accepted: 12/20/2022] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND/AIMS Fexuprazan is a novel potassium-competitive acid blocker that could be of benefit to patients with gastric mucosal injury. The aim of this study was to assess the 2-week efficacy and safety of fexuprazan in patients with acute or chronic gastritis. METHODS In this study, 327 patients with acute or chronic gastritis who had one or more gastric erosions on endoscopy and subjective symptoms were randomized into three groups receiving fexuprazan 20 mg once a day (q.d.), fexuprazan 10 mg twice a day (b.i.d.), or placebo for 2 weeks. The posttreatment assessments were the primary endpoint (erosion improvement rate), secondary endpoints (cure rates of erosion and edema and improvement rates of redness, hemorrhage, and subjective symptoms), and drug-related adverse events. RESULTS Among the patients, 57.8% (59/102), 65.7% (67/102), and 40.6% (39/96) showed erosion improvement 2 weeks after receiving fexuprazan 20 mg q.d., fexuprazan 10 mg b.i.d., and placebo, respectively. Both fexuprazan 20 mg q.d. and 10 mg b.i.d. showed superior efficacy to the placebo (p=0.017 and p<0.001, respectively). Likewise, both fexuprazan 20 mg q.d. and 10 mg b.i.d. also showed higher erosion healing rates than the placebo (p=0.033 and p=0.010, respectively). No difference was noted in the edema healing rate and the improvement rates for redness, hemorrhage, and subjective symptoms between the fexuprazan and placebo groups. No significant difference was noted in the incidence of adverse drug reactions. CONCLUSIONS Fexuprazan 20 mg q.d. and 10 mg b.i.d. for 2 weeks showed therapeutic efficacy superior to that of placebo in patients with acute or chronic gastritis (ClinicalTrials.gov identifier NCT04341454).
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Affiliation(s)
- Gwang Ha Kim
- Department of Internal Medicine, Pusan National University College of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Myung-Gyu Choi
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jin Il Kim
- Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soo Teik Lee
- Department of Internal Medicine, Jeonbuk National University Hospital, Jeonju, Korea
| | - Hoon Jai Chun
- Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea
| | - Kook Lae Lee
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Suk Chei Choi
- Department of Internal Medicine, Wonkwang University Hospital, Wonkwang University College of Medicine, Iksan, Korea
| | - Jae-Young Jang
- Department of Gastroenterology and Hepatology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Gyu Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Ki Bae Kim
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Ki-Nam Shim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Chong Il Sohn
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Kook Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Seok Jang
- Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hwoon-Yong Jung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyojin Park
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyu Chan Huh
- Division of Gastroenterology, Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Su Jin Hong
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Song Baek
- Daewoong Pharmaceutical Co., Ltd., Seoul, Korea
| | - Jin Joo Han
- Daewoong Pharmaceutical Co., Ltd., Seoul, Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
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10
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Zhou S, Xie L, Zhou C, Zhao Y, Wang L, Ding S, Chen J, Zhu B, Su M, Shao F. Keverprazan, a novel potassium-competitive acid blocker: Single ascending dose safety, tolerability, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Eur J Pharm Sci 2023; 190:106578. [PMID: 37666458 DOI: 10.1016/j.ejps.2023.106578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/28/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
BACKGROUND Keverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. AIMS To evaluate the safety, pharmacokinetics, pharmacodynamics, and food effect of single oral doses of keverprazan in healthy Chinese subjects. METHODS In the dose-escalated phase Ia trial, the first 8 subjects received keverprazan 5 mg, the others successively entered 10 mg, 20 mg, 40 mg, 60 mg groups and were randomized to receive keverprazan (n = 8), lansoprazole (LSZ) 30 mg (n = 2) or placebo (n = 2) in each dose group. The phase Ib study randomly enrolled subjects to the fasting-fed (n = 7) or fed-fasting (n = 7) groups for evaluating the food effect of keverprazan. RESULTS Twenty (35.71%) adverse events (AEs) occurred in phase Ia, including 13 (32.50%), 3 (37.50%), and 4 (50.00%) AEs in the keverprazan, placebo, and LSZ groups, respectively. Four (28.57%) AEs occurred in Phase Ib. The Tmax of keverprazan was 1.25-1.75 h. Cmax and AUC increased with the dose, and the t1/2, CL/F were 6.00-7.17 h, 88.8-198 L/h, respectively. The intragastric pH >5 holding-time ratio (HTR) increased with the dose but reached a ceiling at 20 mg. In the 30 mg LSZ and 5-60 mg keverprazan groups, the intragastric pH >5 HTRs during 24 h were 57.1%±26.4%, 7.9%±8.1%, 26.2%±22.8%, 80.2%±8.8%, 88.1%±8.6%, and 93.0%±1.7%, respectively. The geometric mean ratios (90% CI) of Cmax and AUC0-∞ of keverprazan in plasma under the fed vs. fasting state were 126.8% (109.0%-147.5%) and 134.9% (123.8%-146.9%). CONCLUSION Keverprazan is tolerable, and provides significant stable and lasting inhibition efficacy of intragastric acidity at 20 mg.
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Affiliation(s)
- Sufeng Zhou
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Lijun Xie
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Chen Zhou
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Yuqing Zhao
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Lu Wang
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Sijia Ding
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Juan Chen
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Bei Zhu
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China
| | - Mei Su
- Jiangsu Carephar Pharmaceutical Co., Ltd, Nanjing 210000, China.
| | - Feng Shao
- Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing 211166, China.
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11
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Park S, Yang E, Kim B, Kwon J, Jang IJ, Lee SH. Pharmacokinetic and pharmacodynamic exploration of various combinations of tegoprazan immediate and delayed-release formulations. Br J Clin Pharmacol 2023; 89:2877-2887. [PMID: 37170677 DOI: 10.1111/bcp.15784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 04/25/2023] [Accepted: 04/28/2023] [Indexed: 05/13/2023] Open
Abstract
AIMS The new modified-release formulation of tegoprazan, a novel potassium-competitive acid blocker, is expected to improve the management of acid-related disease, including nocturnal acid breakthrough, by prolonging the duration of acid suppression. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of various combinations of tegoprazan with immediate-release (IR) and delayed-release (DR) formulations. METHODS A three-cohort, open-label, randomized, single-dose, three-treatment, six-sequence, three-period crossover study was conducted. Various combinations of tegoprazan IR and DR formulations (50, 75 or 100 mg) were administered orally once per period. The 24-h intragastric pH was monitored before and after each administration. PK blood samples were collected for up to 48 h. PK and PD were compared among treatments. RESULTS Eighteen healthy Korean subjects completed the study. All treatment groups showed intragastric pH above 4 approximately 1 h following tegoprazan administration. Among the various combinations, the IR and DR combination at a 1:1 ratio induced greater gastric acid suppression (%Time pH ≥ 4) than IR alone in each dose group, both for 24 h (50 mg; 59% vs. 52%, P = .2188, 95% confidence interval [CI] -6.92-22.27, 100 mg; 85% vs. 70%, P < .05, 95% CI 8.92-22.19) and at night (50 mg; 27% vs. 16%, P = .1563, 95% CI -11.79-37.71, 100 mg; 77% vs. 49%, P < .05, 95% CI 16.14-42.98), with similar systemic exposure. CONCLUSIONS The combinatorial tegoprazan in the IR and DR 1:1 ratio formulation was found to induce stronger gastric acid suppression throughout the day and at night, compared to the conventional IR formulation.
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Affiliation(s)
- Sooyoun Park
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Eunsol Yang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
- Kidney Research Institute, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Byungwook Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Jihoon Kwon
- Statistics Team, APACE, Seoul, Republic of Korea
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Seung Hwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
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12
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Hwang I, Ji SC, Oh J, Kim H, Cha H, Kim J, Lee CS, Yu KS, Lee S. Randomised clinical trial: Safety, tolerability, pharmacodynamics and pharmacokinetics of zastaprazan (JP-1366), a novel potassium-competitive acid blocker, in healthy subjects. Aliment Pharmacol Ther 2023; 57:763-772. [PMID: 36732884 DOI: 10.1111/apt.17406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/07/2022] [Accepted: 01/19/2023] [Indexed: 02/04/2023]
Abstract
BACKGROUND Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker with favourable preclinical safety and efficacy profile being developed for the treatment of acid-related diseases. AIMS To investigate the safety, tolerability, pharmacodynamics and pharmacokinetics of zastaprazan. METHODS A randomised, open-label, placebo- and active-controlled, single and multiple ascending dose clinical trial was conducted in healthy Korean male subjects. Intragatric pH and serum gastrin were measured to assess the pharmacodynamics, while serial blood and urine samples were collected to assess the pharmacokinetics. Pharmacogenomic evaluation was conducted to explore genetic variants, which can affect the pharmacodynamics and pharmacokinetics. Safety and tolerability including hepatotoxicity were evaluated. RESULTS Suppression of gastric acid secretion increased as the dose of zastaprazan increased. The percentage of time that gastric pH was over 4 (%Time pH >4) with zastaprazan 20 mg (85.19%) and 40 mg (91.84%) were similar to or greater than that with esomeprazole 40 mg (72.06%). Zastaprazan was rapidly absorbed within 2 h and eliminated with a half-life of 6-10 h. Pharmacogenomic analysis found no genetic variant of drug metabolising enzymes including CYP2C19 or drug transporters associated with the exposure of zastaprazan. Zastaprazan was well tolerated with no clinically significant changes in safety and tolerability assessments. CONCLUSIONS Zastaprazan was safe and well tolerated after a single oral dose up to 60 mg and multiple oral doses up to 40 mg. It also showed rapid, potent suppression of gastric acid secretion. Pharmacodynamic and pharmacokinetic profile of zastaprazan was suitable for treatment of patients with acid-related diseases.
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Affiliation(s)
- Inyoung Hwang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Sang Chun Ji
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Jaeseong Oh
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Hyojin Kim
- Onconic Therapeutics Inc., Seoul, Republic of Korea
| | - Hyunju Cha
- Onconic Therapeutics Inc., Seoul, Republic of Korea
| | - John Kim
- Onconic Therapeutics Inc., Seoul, Republic of Korea
| | | | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - SeungHwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
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13
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Cho YK, Kim JH, Kim H, Kim T, Oh J, Choi SC, Moon JS, Lee SK, Jung SW, Kim SS, Jung H, Lee SP, Cheon G, Park MI, Jung H, Ko KH, Sung IK, Lee SH, Lee JY, Lee ST, Rhee P, Kim N, Hong SJ, Kim HJ, Kim GH, Lee KJ, Kim SK, Shin WG, Lee OY. Randomised clinical trial: comparison of tegoprazan and lansoprazole as maintenance therapy for healed mild erosive oesophagitis. Aliment Pharmacol Ther 2023; 57:72-80. [PMID: 36314172 PMCID: PMC10092320 DOI: 10.1111/apt.17255] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/08/2022] [Accepted: 10/06/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Tegoprazan is a novel potassium-competitive acid blocker used to treat acid-related disorders. AIM To compare tegoprazan 25 mg with lansoprazole 15 mg as maintenance therapy in healed erosive oesophagitis (EE) METHODS: In this phase 3, double-blind, multi-centre study, patients with endoscopically confirmed healed EE were randomised 1:1 to receive tegoprazan 25 mg or lansoprazole 15 mg once daily for up to 24 weeks. The primary efficacy endpoint was the endoscopic remission rate after 24 weeks. The secondary efficacy endpoint was the endoscopic remission rate after 12 weeks. Safety endpoints included adverse events, clinical laboratory results and serum gastrin and pepsinogen I/II levels. RESULTS We randomised patients to tegoprazan 25 mg (n = 174) or lansoprazole 15 mg (n = 177). Most had mild EE (Los Angeles (LA) grade A: 57.3%, LA grade B: 37.3%). The endoscopic remission rate after 24 weeks was 90.6% with tegoprazan and 89.5% with lansoprazole. Tegoprazan was not inferior to lansoprazole for maintaining endoscopic remission at 24 weeks and 12 weeks. In subgroup analysis, tegoprazan 25 mg showed no significant difference in maintenance rate according to LA grade (p = 0.47). The maintenance effect of tegoprazan was consistent in CYP2C19 extensive metabolisers (p = 0.76). Increases in serum gastrin were not higher in tegoprazan-treated than lansoprazole-treated patients. CONCLUSIONS Tegoprazan 25 mg was non-inferior to lansoprazole 15 mg in maintenance of healing of mild EE. In this study, tegoprazan had a similar safety profile to lansoprazole.
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Affiliation(s)
- Yu Kyung Cho
- Catholic Photomedicine Research Institute, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Jae Hak Kim
- Department of Internal MedicineDongguk University Ilsan Hospital, Dongguk University College of MedicineGoyangSouth Korea
| | - Hyun‐Soo Kim
- Department of Internal MedicineYonsei University Wonju College of Medicine, Wonju Christian HospitalWonjuSouth Korea
| | - Tae‐Oh Kim
- Department of Internal MedicineInje University Haeundae Paik HospitalBusanSouth Korea
| | - Jung‐Hwan Oh
- Department of Internal MedicineEunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of KoreaSeoulSouth Korea
| | - Suck Chei Choi
- Department of Internal MedicineWonkwang University HospitalIksanSouth Korea
| | - Jeong Seop Moon
- Department of Internal MedicineInje University, Seoul Paik HospitalSeoulSouth Korea
| | - Sang Kil Lee
- Department of Internal MedicineYonsei University College of Medicine, Severance HospitalSeoulSouth Korea
| | - Sung Woo Jung
- Department of Internal MedicineKorea University College of MedicineSeoulSouth Korea
| | - Sung Soo Kim
- Department of Internal MedicineUijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of KoreaUijeongbuSouth Korea
| | - Hye‐Kyung Jung
- Department of Internal MedicineCollege of Medicine, Ewha Womans UniversitySeoulSouth Korea
| | - Sang Pyo Lee
- Department of Internal MedicineHallym University Dongtan Sacred Heart HospitalHwaseongSouth Korea
| | - Gab‐Jin Cheon
- Department of Internal MedicineGangNeung Asan Hospital, College of Medicine, Ulsan UniversityGangneungSouth Korea
| | - Moo In Park
- Department of Internal MedicineKosin University College of MedicineBusanSouth Korea
| | - Hwoon‐Yong Jung
- Department of GastroenterologyAsan Medical Center, University of UlsanSeoulSouth Korea
| | - Kwang Hyun Ko
- Digestive Disease CenterCHA Bundang Medical Center, CHA UniversitySeongnamSouth Korea
| | - In Kyung Sung
- Department of Internal MedicineKonkuk University Medical CenterSeoulSouth Korea
| | - Si Hyung Lee
- Department of Internal MedicineYeungnam University College of MedicineDaeguSouth Korea
| | - Ju Yup Lee
- Department of Internal MedicineKeimyung University School of MedicineDaeguSouth Korea
| | - Soo Teik Lee
- Department of Internal MedicineJeonbuk National University HospitalJeonjuSouth Korea
| | - Poong‐Lyul Rhee
- Department of MedicineSamsung Medical Center, Sungkyunkwan UniversitySeoulSouth Korea
| | - Nayoung Kim
- Department of Internal MedicineSeoul National University Bundang Hospital, Seongnam and Seoul National University College of MedicineSeoulSouth Korea
| | - Su Jin Hong
- Department of Internal MedicineSoonchunhyang University College of MedicineBucheonSouth Korea
| | - Hyun Jin Kim
- Department of Internal MedicineGyeongsang National University Changwon HospitalChangwonSouth Korea
| | - Gwang Ha Kim
- Department of Internal MedicinePusan National University College of Medicine and Biomedical Research Institute, Pusan National University HospitalBusanSouth Korea
| | - Kwang Jae Lee
- Department of GastroenterologyAjou University Hospital, Ajou University School of MedicineSuwonSouth Korea
| | - Sung Kook Kim
- Department of Internal MedicineKyungpook National University HospitalDaeguSouth Korea
| | - Woon Geon Shin
- Department of Internal MedicineHallym University College of Medicine/Institute for Liver and Digestive DiseasesChuncheonSouth Korea
| | - Oh Young Lee
- Department of Internal MedicineHanyang University College of MedicineSeoulSouth Korea
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14
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Zhou W, Chen X, Fan Q, Yu H, Jiang W. Using proton pump inhibitors increases the risk of hepato-biliary-pancreatic cancer. A systematic review and meta-analysis. Front Pharmacol 2022; 13:979215. [PMID: 36188583 PMCID: PMC9515471 DOI: 10.3389/fphar.2022.979215] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background: More and more studies are focusing on the adverse effects and damage caused by PPI abuse, we carried out a systematic review and meta-analysis for assessing whether the proton pump inhibitor (PPI) leads to hepato-biliary-pancreatic cancer. Methods: PubMed, EMBASE and Web of Science were searched until 1 July 2022, 25 studies (17 case-control and 8 cohort studies; 2741853 individuals) included in this study. Pooled Odd Ratios (ORs) were used for random effect models. Sensitivity analysis and dose-response analysis, subgroup analysis were all conducted. Results: The aggregate OR of the meta-analysis was 1.69 (95% confidence interval (CI): 1.42–2.01, p = 0.01) and heterogeneity (I2 = 98.9%, p < 0.001) was substantial. According to stratified subgroup analyses, the incidence of hepato-biliary-pancreatic cancer was associated, expect for study design, study quality and region. Risk of hepato-biliary-pancreatic cancer is highest when people is treated with normal doses of PPI. The risks decrease and become insignificant when the cumulative defined daily dose (cDDD) increases. Conclusion: The use of PPI may be associated with an increased risk of hepato-biliary-pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of hepato-biliary-pancreatic cancer.
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Affiliation(s)
- Wence Zhou
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, Gansu, China
- *Correspondence: Wence Zhou,
| | - Xinlong Chen
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Qigang Fan
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Haichuan Yu
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Wenkai Jiang
- First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of General Surgery, First Hospital of Lanzhou University, Lanzhou, Gansu, China
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15
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Leowattana W, Leowattana T. Potassium-competitive acid blockers and gastroesophageal reflux disease. World J Gastroenterol 2022; 28:3608-3619. [PMID: 36161043 PMCID: PMC9372813 DOI: 10.3748/wjg.v28.i28.3608] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/24/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors (PPIs), the most commonly used antisecretory medi-cations in the management of reflux illness, virtually eliminate elective surgery for ulcer disease, and relegate anti-reflux surgery to patients with gastroesophageal reflux disease (GERD) who are inadequately managed by medical therapy. However, PPI medications still leave some therapeutic demands of GERD unmet. Furthermore, up to 40%-55% of daily PPI users have chronic symptoms, due to PPI refractoriness. Potassium-competitive acid blockers (P-CABs) transcend many of the problems and limits of PPIs, delivering quick, powerful, and extended acid suppression and allowing for treatment of numerous unmet needs. Recently, it has become clear that compromised mucosal integrity plays a role in the etiology of GERD. As a result, esophageal mucosal protection has emerged as a novel and potential treatment approach. An increasing body of research demonstrates that when P-CABs are used as primary drugs or add-on drugs (to regular treatment), they provide a considerable extra benefit, particularly in alleviating symptoms that do not respond to PPI therapy.
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Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
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16
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Yang E, Kim S, Kim B, Kim B, Kim Y, Park SS, Song GS, Yu KS, Jang IJ, Lee SH. Night-time gastric acid suppression by tegoprazan compared to vonoprazan or esomeprazole. Br J Clin Pharmacol 2022; 88:3288-3296. [PMID: 35146797 PMCID: PMC9305887 DOI: 10.1111/bcp.15268] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/18/2022] [Accepted: 01/26/2022] [Indexed: 11/26/2022] Open
Abstract
AIM Nocturnal acid breakthrough has been considered an unmet need of proton pump inhibitors. Tegoprazan, a novel potassium-competitive acid blocker, is expected to show improved properties for this unmet need. This study was aimed to compare night-time acid suppression by tegoprazan with that by vonoprazan or esomeprazole, and to explore the effect of CYP2C19 phenotypes on acid-suppressive effects. METHODS A randomized, open-label, three-period, six-sequence crossover study was conducted. A single oral dose of tegoprazan 50 mg, vonoprazan 20 mg or esomeprazole 40 mg was administered at night in each period. Continuous intragastric pH was monitored at baseline and after each dosing. RESULTS 16 healthy subjects (6 CYP2C19 extensive metabolizers, 5 intermediate metabolizers, 5 poor metabolizers) completed the study. After a single dose of tegoprazan, intragastric pH increased more rapidly to over 4 at approximately 1 hour compared to the other treatments, and elevated intragastric pH was maintained stably at night. Tegoprazan exhibited night-time acid suppression for slightly but not significantly longer than vonoprazan, and greater than esomeprazole; % Time pH ≥4 at night-time was 66.0%, 60.5% and 36.1% for tegoprazan, vonoprazan and esomeprazole, respectively. Night-time acid suppression by tegoprazan and vonoprazan was not dependent on CYP2C19 phenotypes, while that by esomeprazole tended to be influenced by CYP2C19 phenotypes. CONCLUSIONS Tegoprazan produced more rapid, potent and well sustained night-time acid suppression versus vonoprazan or esomeprazole when administered at night. Furthermore, tegoprazan showed no CYP2C19 phenotype dependency in acid suppression. It suggests the potential of tegoprazan, especially in preventing nocturnal acid breakthrough.
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Affiliation(s)
- Eunsol Yang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Seokuee Kim
- Division of Clinical Development, HK inno. N Corp., Seoul, Republic of Korea
| | - Bongtae Kim
- Division of Clinical Development, HK inno. N Corp., Seoul, Republic of Korea
| | - Boram Kim
- Department of Laboratory Medicine, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Yechan Kim
- Department of Laboratory Medicine, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Sung Sup Park
- Department of Laboratory Medicine, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Geun Seog Song
- Division of Clinical Development, HK inno. N Corp., Seoul, Republic of Korea
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Seung Hwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
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17
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Hwang S, Ko JW, Lee H, Kim S, Kim B, Song GS, Kim J. Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects. Front Pharmacol 2021; 12:754849. [PMID: 34867368 PMCID: PMC8632694 DOI: 10.3389/fphar.2021.754849] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 10/20/2021] [Indexed: 01/03/2023] Open
Abstract
Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.
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Affiliation(s)
- Sejung Hwang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea
| | - Jae-Wook Ko
- Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, South Korea
| | - Heechan Lee
- Division of Clinical Development, HK Inno.N Corporation, Seoul, South Korea
| | - Seokuee Kim
- Division of Clinical Development, HK Inno.N Corporation, Seoul, South Korea
| | - Bongtae Kim
- Division of Clinical Development, HK Inno.N Corporation, Seoul, South Korea
| | - Geun Seog Song
- Division of Clinical Development, HK Inno.N Corporation, Seoul, South Korea
| | - Jungryul Kim
- Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, South Korea.,Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea
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18
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Kim SH, Cho KB, Chun HJ, Lee SW, Kwon JG, Lee DH, Kim SG, Jung H, Kim JW, Lee JS, Park H, Choi SC, Jee SR, Kim H, Ko KH, Park SJ, Lee YC, Park SH, Kim AR, Kim EJ, Park HW, Kim BT, Song GS. Randomised clinical trial: comparison of tegoprazan and placebo in non-erosive reflux disease. Aliment Pharmacol Ther 2021; 54:402-411. [PMID: 34227708 PMCID: PMC8361733 DOI: 10.1111/apt.16477] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 02/23/2021] [Accepted: 05/20/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Tegoprazan is a novel, fast- and long-acting potassium-competitive acid blocker that suppresses gastric acid secretion, which could benefit patients with non-erosive reflux disease (NERD), a type of gastroesophageal reflux disease. AIM To evaluate the efficacy and safety profiles of tegoprazan compared with those of a placebo in Korean patients with NERD. METHODS In this phase 3, double-blind, placebo-controlled, multicentre study, 324 Korean patients with NERD were randomised into three treatment groups: tegoprazan 50 mg, tegoprazan 100 mg and placebo. These drugs were provided once daily for 4 weeks. The primary endpoint was the proportion of patients with complete resolution of major symptoms (both heartburn and regurgitation) for the last 7 days of the 4-week treatment period. Other outcomes related to efficacy, safety and tolerability were also evaluated. RESULTS Among all, 42.5% (45/106), 48.5% (48/99) and 24.2% (24/99) of patients showed complete resolution of major symptoms at week 4 after receiving tegoprazan 50 mg, tegoprazan 100 mg, and placebo, respectively. Both doses of tegoprazan showed superior efficacy than the placebo (P = 0.0058 and P = 0.0004, respectively). The complete resolution rates of heartburn and proportions of heartburn-free days (as other efficacy outcomes) were significantly higher in both tegoprazan groups than in the placebo group (P < 0.05 for all). No significant difference in the incidence of treatment-emergent adverse events were noted. CONCLUSIONS Tegoprazan 50 and 100 mg showed superior therapeutic efficacy compared with the placebo, as well as a favourable safety profile in patients with NERD. Registration number: ClinicalTrials.gov identifier NCT02556021.
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19
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Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans. Pharmaceutics 2021; 13:pharmaceutics13060813. [PMID: 34072547 PMCID: PMC8229463 DOI: 10.3390/pharmaceutics13060813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/26/2021] [Accepted: 05/27/2021] [Indexed: 12/26/2022] Open
Abstract
Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29-2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4-38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.
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