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Vonoprazan Fumarate Sale

(Synonyms: 富马酸沃诺拉赞; TAK-438) 目录号 : GC61374

A selective and reversible proton pump inhibitor

Vonoprazan Fumarate Chemical Structure

Cas No.:881681-01-2

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产品描述

Vonoprazan is a selective, reversible, and potassium-competitive proton pump inhibitor that inhibits gastric H+/K+ ATPase (IC50 = 17 nM) but does not inhibit porcine Na+/K+ ATPase activity when used at a concentration of 10 ?M.1,2 It maintains its inhibitory effect in both weakly acidic (pH 6.5) and neutral (pH 7.5) conditions with IC50 values of 19 and 28 nM, respectively. In vivo, vonoprazan (1, 2, and 4 mg/kg) inhibits histamine-stimulated acid secretion in a dose-dependent manner in rats, with complete inhibition when administered at a dose of 4 mg/kg.3 It also inhibits acid secretion for more than 48 hours in dogs when administered at doses ranging from 0.1 to 1 mg/kg.

1.Shin, J.M., Inatomi, N., Munson, K., et al.Characterization of a novel potassium-competitive acid blocker of the gastric H,K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438)J. Pharmacol. Exp. Ther.339(2)412-420(2011) 2.Hori, Y., Imanishi, A., Matsukawa, J., et al.1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseasesJ. Pharmacol. Exp. Ther.335(1)231-238(2010) 3.Hori, Y., Matsukawa, J., Takeuchi, T., et al.A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animalsJ. Pharmacol. Exp. Ther.337(3)797-804(2011)

Chemical Properties

Cas No. 881681-01-2 SDF
别名 富马酸沃诺拉赞; TAK-438
Canonical SMILES O=C(O)/C=C/C(O)=O.O=S(N1C=C(CNC)C=C1C2=CC=CC=C2F)(C3=CC=CN=C3)=O.[(E)]
分子式 C21H20FN3O6S 分子量 461.46
溶解度 DMSO: 50 mg/mL (108.35 mM) 储存条件 Store at -20°C
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1 mM 2.167 mL 10.8352 mL 21.6704 mL
5 mM 0.4334 mL 2.167 mL 4.3341 mL
10 mM 0.2167 mL 1.0835 mL 2.167 mL
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Research Update

Vonoprazan Fumarate, a novel potassium-competitive acid blocker, in the management of gastroesophageal reflux disease: safety and clinical evidence to date

Therap Adv Gastroenterol 2018 Jan 9;11:1756283X17745776.PMID:29383028DOI:10.1177/1756283X17745776.

Potassium-competitive acid blocker (P-CAB) is a class of drug that competitively blocks the potassium-binding site of H+, K+-adenosine triphosphate (ATP)ase. Although the history of this class of drugs started over 30 years ago, clinical use of two P-CABs, revaprazan and vonoprazan, were only recently approved in Korea and Japan, respectively. Among them, vonoprazan has several advantages over conventional proton-pump inhibitors (PPIs), including rapid onset of action, long duration of acid suppression, fewer interindividual variations in terms of acid suppression, and minimum dietary influence on its action. These advantages of vonoprazan have been proved in clinical trials conducted for license approvals for several acid-related diseases. In this review article, current evidence of vonoprazan in the management of gastroesophageal reflux disease (GERD) will be summarized. Since the clinical trial data, as well as postmarketed clinical data, have consistently demonstrated superiority of vonoprazan over conventional PPIs in terms of achieving healing of mucosal breaks and maintaining the healing, it may provide an excellent, if not complete, option for fulfilling some of the unmet needs for current GERD therapy. The safety problem of vonoprazan is also discussed, as more pronounced hypergastrinemia inevitably ensues with its use.

The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic Considerations

Clin Pharmacokinet 2016 Apr;55(4):409-18.PMID:26369775DOI:10.1007/s40262-015-0326-7.

Vonoprazan Fumarate (Takecab) is a first-in-class potassium-competitive acid blocker that has been available in the market in Japan since February 2015. Vonoprazan is administered orally at 20 mg once daily for the treatment of gastroduodenal ulcer, at 20 and 10 mg once daily for the treatment and secondary prevention of reflux esophagitis, respectively, at 10 mg once daily for the secondary prevention of low-dose aspirin- or non-steroidal anti-inflammatory drug-induced peptic ulcer, and at 20 mg twice daily in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori. It inhibits H(+),K(+)-ATPase activities in a reversible and potassium-competitive manner with a potency of inhibition approximately 350 times higher than the proton pump inhibitor, lansoprazole. Vonoprazan is absorbed rapidly and reaches maximum plasma concentration at 1.5-2.0 h after oral administration. Food has minimal effect on its intestinal absorption. Oral bioavailability in humans remains unknown. The plasma protein binding of vonoprazan is 80% in healthy subjects. It distributes extensively into tissues with a mean apparent volume of distribution of 1050 L. Being a base with pKa of 9.6 and with acid-resistant properties, vonoprazan is highly concentrated in the acidic canaliculi of the gastric parietal cells and elicited an acid suppression effect for longer than 24 h after the administration of 20 mg. The mean apparent terminal half-life of the drug is approximately 7.7 h in healthy adults. Vonoprazan is metabolized to inactive metabolites mainly by cytochrome P450 (CYP)3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1. A mass balance study showed that 59 and 8% of the orally administered radioactivity was recovered in urine as metabolites and in an unchanged form, respectively, indicating extensive metabolism. Genetic polymorphism of CYP2C19 may influence drug exposure but only to a clinically insignificant extent (15-29%), according to the population pharmacokinetic study performed in Japanese patients. When vonoprazan was co-administered with clarithromycin, the mean AUC from time 0 to time of the next dose (dosing interval) of vonoprazan and clarithromycin were increased by 1.8 and 1.5 times, respectively, compared with the corresponding control values, indicating mutual metabolic inhibition. The mean area under the curve from time zero to infinity obtained from patients with severe liver and renal dysfunction were elevated by 2.6 and 2.4 times, respectively, compared with healthy subjects, with no significant changes in plasma protein binding. Vonoprazan increases intragastric pH above 4.0 as early as 4 h after an oral dose of 20 mg, and the extensive anti-secretory effect is maintained up to 24 h post-dose. During repeated dosing of 20 mg once daily, the 24-h intragastric pH >4 holding time ratios were 63 and 83 % on days 1 and 7, respectively. Because vonoprazan elicited a more extensive gastric acid suppression than the proton pump inhibitor, lansoprazole, it also gave rise to two to three times greater serum gastrin concentrations as compared with lansoprazole. In pre-approval clinical studies for the treatment of acid-related disorders, mild to moderate adverse drug reactions (mostly constipation or diarrhea) occurred at frequencies of 8-17%. Neither severe liver toxicity nor neuroendocrine tumor has been reported in patients receiving vonoprazan.

Vonoprazan Fumarate for the management of acid-related diseases

Expert Opin Pharmacother 2017 Aug;18(11):1145-1152.PMID:28657473DOI:10.1080/14656566.2017.1346087.

Proton pump inhibitors (PPIs) display a number of limitations and unmet clinical needs that have prompted the development of novel drugs to improve the outcomes of acid-related diseases, including the eradication of H. pylori. In this context, a new synthesized potassium-competitive acid blocker (P-CAB), vonoprazan, showed higher suppression of gastric acid secretion. Areas covered: This review discusses the current knowledge regarding the efficacy of vonoprazan in the treatment of acid-related diseases, with a particular focus on its use in Helicobacter pylori eradication. Expert opinion: Vonoprazan showed some advantages over PPIs in terms of the pharmacokinetic and pharmacodynamic profile: fast onset of action without requiring acid activation and specific administration timing, more potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability. Recent evidence suggests that vonoprazan can be preferred to PPIs as maintenance therapy for reflux esophagitis and eradication of Helicobacter pylori owing to its stronger antisecretory effect. Moreover, vonoprazan displays favorable safety and tolerability profiles, even though long-term studies on the effects of vonoprazan are required.

Vonoprazan Fumarate for the Treatment of Gastric Ulcers: A Short Review on Emerging Data

Clin Exp Gastroenterol 2020 Apr 15;13:99-104.PMID:32346304DOI:10.2147/CEG.S228352.

Potassium-competitive acid blockers (P-CABs), such as vonoprazan, represent a novel and heterogeneous class of drugs that competitively block the potassium binding site of gastric H+/K+ ATPase, thus potentially overcoming the limitations of proton-pump inhibitors. Different studies evaluated the efficacy of vonoprazan versus proton-pump inhibitors (PPIs) for the treatment of acid-related disorders, and, therefore, P-CABs present the same indications of PPIs: gastroesophageal reflux disease, gastric and duodenal ulcer healing, management of upper gastrointestinal bleeding, non-steroidal anti-inflammatory drug (NSAID)-associated ulcers and Helicobacter pylori eradication therapy. The aim of this review was to evaluate the role of vonoprazan for the treatment of peptic ulcer disease (PUD) and the management of gastric ulcer occurring after endoscopic submucosal dissection (ESD). Indeed, vonoprazan (at the dose of both 10 and 20mg) showed similar results to PPIs in patients taking long-term NSAIDs, in the absence of severe adverse effects, and provided a more rapid and effective treatment of ulcers induced by ESD. However, studies in medical literature are heterogeneous, mainly performed with a retrospective design, and often carried out in Japan only. For these reasons, further prospective, randomized studies are warranted in order to help physicians, patients, and policymakers regarding the use of vonoprazan in clinical practice.

The Effects of Vonoprazan Fumarate on the Tacrolimus Blood Concentration in Liver Transplant Recipients

Cancer Diagn Progn 2022 Sep 3;2(5):553-557.PMID:36060027DOI:10.21873/cdp.10141.

Background/aim: The proton pump inhibitors were reported to affect the blood concentration of tacrolimus. Vonoprazan Fumarate is a new acid suppressant with potent acid inhibitory effects. There have been no reports concerning the effect of vonoprazan on the tacrolimus blood concentration in liver transplant (LT) recipients. Patients and methods: Eighteen living donor liver transplantation (LDLT) recipients who switched from proton pump inhibitors (PPIs) to vonoprazan between 2016 to 2018 were enrolled in this retrospective study. We investigated blood levels of tacrolimus, and liver and renal function before and after the change from PPIs to vonoprazan. Results: The median C 0 /D of tacrolimus before conversion, 3 months after conversion, and 6 months after conversion were 2.33, 1.53, and 1.89, respectively, and there was no significant difference. Conversion from another PPI to vonoprazan was not associated with a worsening liver function. The estimated glomerular filtration rate was significantly worse after conversion. Conclusion: Vonoprazan can be safely administered to LT recipients receiving tacrolimus during the stable period.