Ilaprazole

Ilaprazole (IY-81149) is a proton pump inhibitor; inhibits H+/K+-ATPase with an IC50 of 6.0 μM.

In Vitro:In rabbit parietal cells, ilaprazole irreversibly inhibits H+/K+-ATPase in dose-dependent manner with an IC50 of pump inhibitory activity of 6.0 μM. The IC50 of ilaprazole is 9.0 nM on cumulation of 14C-aminopyrine in histamine stimulated parietal cells[1].

In Vivo:In pylorus-ligated rats, ilaprazole shows strong inhibitory activity against gastric acid secretion. The ED50 of ilaprazole administered intraduodenally is 1.6 mg/kg. For oral administration, the ED50 of ilaprazole is 1.94 mg/kg. Ilaprazole also significantly inhibits pentagastrin-stimulated gastric secretion. Its ED50 is 2.1 mg/kg. In Heidenhain pouch dogs, the acid output is completely blocked at 0.3 mg/kg, 135 min after i.v. administration[1]. Intravenous ilaprazole exhibits high antiulcer activity in a dose-dependent manner. Ilaprazole at a dose of 3 mg/kg decreases ulcer number and index to the same extent as 20 mg/kg esomeprazole. Moreover, the potency of intravenous ilaprazole is superior to that of intragastric ilaprazole. In anesthetized rats, the inhibitory effect of intravenous ilaprazole on histamine-induced acid secretion is faster and longer-lasting than that of intraduodenal ilaprazole[2].

References:
[1]. Kwon D, et al. Effects of IY-81149, a newly developed proton pump inhibitor, on gastric acid secretion in vitro and in vivo. Arzneimittelforschung. 2001;51(3):204-13. [2]. Yu G, et al. Intravenous ilaprazole is more potent than oral ilaprazole against gastric lesions in rats. Dig Dis Sci. 2014 Oct;59(10):2417-22.

Ilaprazole Compared With Rabeprazole in the Treatment of Duodenal Ulcer: A Randomized, Double-blind, Active-controlled, Multicenter Study.[Pubmed:30789856]

J Clin Gastroenterol. 2019 Feb 15.

GOALS: The main goal of this study was to explore the dose-effect relationship of Ilaprazole. BACKGROUND: Ilaprazole is a kind of benzimidazole proton-pump inhibitor, which was confirmed efficacious and safe in treatment of duodenal ulcer (DU). However, the dose-effect relationship of Ilaprazole was not clear. STUDY: This was a double-blind, parallel, randomized study. Patients aged above 18 years with at least one endoscopically confirmed active nonmalignant DU were treated with rabeprazole 10 mg or Ilaprazole 10 mg/5 mg for 4 weeks. Healing of ulcer was determined by its resolution from active to scarring stage. Symptoms relief was evaluated using a graded score. Safety and tolerability were evaluated on basis of clinical assessments. RESULTS: A total of 390 patients completed the study finally. Ulcers were successfully healed in 75.38%, 77.86%, and 83.72% of patients after 4-week treatment with rabeprazole 10 mg, Ilaprazole 5 mg, and Ilaprazole 10 mg, respectively. The 4-week healing rate difference between rabeprazole 10 mg and Ilaprazole 5 mg was 2.48% (95% confidence interval: -7.79% to 12.74%) leading to accept the noninferiority hypothesis. Logistic regression model suggested that Ilaprazole 10 mg was superior to Ilaprazole 5 mg at week 2 (odds ratio, 1.92; 95% confidence interval: 1.02, 3.59; P=0.04). Most patients (80%) became asymptomatic after treatment. At the dosages administered, the 3 drug groups exhibited similar efficacy and a similar safety profile. CONCLUSIONS: Ilaprazole 5 mg is not inferior to rabeprazole 10 mg in treating DU, and a dose-effect relationship have been revealed between 5 mg and 10 mg of Ilaprazole.

Prospective Single Arm Study on the Effect of Ilaprazole in Patients with Heartburn but No Reflux Esophagitis.[Pubmed:30187702]

Yonsei Med J. 2018 Oct;59(8):951-959.

PURPOSE: Patients with gastroesophageal reflux disease without esophagitis show varying responses to proton pump inhibitors (PPIs). The aim of this study was to objectively evaluate the effect of a new PPI, Ilaprazole, on patients with heartburn but without reflux esophagitis. MATERIALS AND METHODS: This prospective study was performed on 20 patients with heartburn but without reflux esophagitis. All patients underwent upper endoscopy and 24-hr combined multichannel intraluminal impedance and pH esophageal monitoring (MII-pH). They were then treated with Ilaprazole (20 mg) once daily for 4 weeks. The GerdQ questionnaire, histologic findings, and inflammatory biomarkers were used for assessment before and after Ilaprazole. RESULTS: Among the 20 patients, 13 (65%) showed GerdQ score >/=8. Based on MII-pH results, patients were classified as true nonerosive reflux disease (n=2), hypersensitive esophagus (n=10), and functional heartburn (n=8). After treatment, patients showed a statistically significant improvement in GerdQ score (p<0.001). Among histopathologic findings, basal cell hyperplasia, papillary elongation, and infiltration of intraepithelial T lymphocytes improved significantly (p=0.008, p=0.021, and p=0.008; respectively). Expression of TNF-alpha, IL-8, TRPV1, and MCP-1 decreased marginally after treatment (p=0.049, p=0.046, p=0.045, and p=0.042; respectively). CONCLUSION: Daily Ilaprazole (20 mg) is efficacious in improving symptom scores, histopathologic findings, and inflammatory biomarkers in patients with heartburn but no reflux esophagitis.

Biotransformation of Ilaprazole in Human Liver Microsomes and Human: Role of CYP3A4 in Ilaprazole Clearance and Drug-Drug Interaction.[Pubmed:30002078]

Drug Metab Dispos. 2018 Oct;46(10):1453-1461.

Ilaprazole is a new proton pump inhibitor and is currently marketed in China and South Korea for the treatment of gastric and duodenal ulcer. Ilaprazole has a favorable long half-life and minimal pharmacokinetic variability associated with CYP2C19 polymorphism. Sulfoxide oxidation of Ilaprazole is catalyzed mainly by CYP3A4. Thus, it has been widely accepted that CYP3A4 plays a major role in the clearance of Ilaprazole in humans. However, absorption, distribution, metabolism, and excretion data of radiolabeled Ilaprazole in humans are not available. The primary goal of this study was to determine if sulfoxide oxidation is a major metabolic pathway of Ilaprazole in humans. Metabolite profiles of Ilaprazole, Ilaprazole sulfide, and Ilaprazole sulfone in human liver microsomes (HLMs) were characterized and quantitively analyzed by liquid chromatography (LC)/UV/high-resolution mass spectrometry (HRMS). Moreover, metabolites of Ilaprazole in human urine and feces were detected and identified by LC-HRMS. The results revealed that sulfoxide reduction to Ilaprazole sulfide rather than sulfoxide oxidation was the major biotransformation pathway in HLMs. Sulfoxide reduction also occurred in HLMs without NADPH or in deactivated HLMs. Ilaprazole sulfide and its multiple oxidative metabolites were major drug-related components in human urine and feces, where there were no Ilaprazole sulfone and its metabolites. A small amount of the parent drug was found in feces. Thus, we propose that nonenzymatic sulfoxide reduction rather than CYP3A4-medidated sulfoxide oxidation is the major metabolic clearance pathway of Ilaprazole in humans. Consequently, it is predicted that Ilaprazole has no significant drug-drug interaction via CYP3A4 inhibition or induction by a coadministered drug.

Pharmacokinetic drug interaction and safety after coadministration of clarithromycin, amoxicillin, and ilaprazole: a randomised, open-label, one-way crossover, two parallel sequences study.[Pubmed:29846770]

Eur J Clin Pharmacol. 2018 Sep;74(9):1149-1157.

PURPOSE: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and Ilaprazole. METHODS: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of Ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and Ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of Ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted. RESULTS: Twenty-eight subjects completed the study. For Ilaprazole, the peak concentration (Cmax) slightly decreased from 479 (Ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUClast) slightly increased from 3301 to 3538 mug.h/mL [1.07 (0.85-1.35)]. For clarithromycin, the Cmax slightly decreased from 1.87 to 1.72 mug/mL [0.90 (0.70-1.15)], and AUClast slightly increased from 14.6 to 16.5 mug.h/mL [1.09 (0.87-1.37)]. For amoxicillin, the Cmax slightly decreased from 9.37 to 8.14 mug/mL [0.86 (0.74-1.01)], and AUClast slightly decreased from 27.9 to 26.7 mug.h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant. CONCLUSIONS: The coadministration of Ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising Ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Efficacy and Safety of the Triple Therapy Containing Ilaprazole, Levofloxacin, and Amoxicillin as First-Line Treatment in Helicobacter pylori Infections.[Pubmed:28539935]

Gastroenterol Res Pract. 2017;2017:1654907.

Background and Aims. To establish the efficacy and safety of Ilaprazole, levofloxacin, and amoxicillin as a first-line eradication treatment for Helicobacter pylori. Methods. Patients with gastric ulcer, duodenal ulcer, or gastritis, as detected by esophagogastroduodenoscopy with confirmed H. pylori infection between September 2014 and November 2015, were enrolled in the study. All participants received Ilaprazole (10 mg bid), levofloxacin (500 mg bid), and amoxicillin (1000 mg bid) for 10 days. H. pylori eradication was confirmed by a (13)C-urea breath test at 6-8 weeks after the end of treatment. Results. Of 84 patients included in the analysis, the eradication rate was 88.8% in the per protocol group (n = 80). Demographic factors such as age, gender, body mass index (BMI), alcohol, smoking, hypertension, diabetes mellitus, and peptic ulcer did not affect the eradication rate. However, multivariate analysis showed that overweight patients and patients with cerebrovascular accident (CVA) had a significantly lower eradication rate than patients with normal BMI and without CVA. Laboratory test results did not change significantly after treatment. A total of six (7.5%) patients developed eight adverse reactions. Conclusions. A 10-day triple therapy containing Ilaprazole, levofloxacin, and amoxicillin is a safe alternative first-line eradication treatment for H. pylori.

Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase.[Pubmed:28388576]

Oncotarget. 2017 Jun 13;8(24):39143-39153.

T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that Ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that Ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to Ilaprazole. Results of an in vivo study demonstrated that gavage of Ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after Ilaprazole treatment. Our results suggested that Ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo.

Development of Solid-Phase Extraction and HPLC Method for Simultaneous Estimation of Ilaprazole and Glimepiride in Rat Plasma: Application to Pharmacokinetic Studies.[Pubmed:28069690]

J Chromatogr Sci. 2017 Mar 1;55(3):327-333.

A novel, simple and mass spectrometry (MS) compatible high-performance liquid chromatography (HPLC) method is reported for the simultaneous estimation of Ilaprazole (ILA) and glimepiride (GLM) in rat plasma. The bio-analytical procedure involves extraction of ILA, GLM and internal standard (IS) from rat plasma with a solid-phase extraction (SPE) process. The chromatographic analysis was performed on Waters-600 system using an isocratic mobile phase comprising methanol:water (80:20 % v/v) with pH of water modified to three using formic acid at a flow rate of 1.0 mL/min and Kinetex C18 column maintained at 30 +/- 1 degrees C. The signals were monitored using a PDA detector set at 225 nm. IS, ILA and GLM eluted at 2.04, 4.7 and 7.4 min, respectively, and the total run time was 10 min. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. The calibration curve was linear over a concentration range of 10-600 ng/mL (r2 = 0.999). The intra- and inter-day precisions for ILA and GLM were (%RSD values) in the range of 1.52-9.74 and 1.52-11.76%, respectively, in rat plasma. The method was successfully applied in pharmacokinetic studies followed by oral administration of GLM and ILA in rats.

Modeling the cost-effectiveness of ilaprazole versus omeprazole for the treatment of newly diagnosed duodenal ulcer patients in China.[Pubmed:27223846]

J Med Econ. 2016 Nov;19(11):1056-1060.

OBJECTIVES: To evaluate the cost-effectiveness of 10 mg Ilaprazole once-daily vs 20 mg omeprazole once-daily to treat newly-diagnosed duodenal ulcer patients in China. METHODS: A decision tree model was constructed and the treatment impact was projected up to 1 year. The CYP2C19 polymorphism distribution in the Chinese population, the respective cure rates in the CYP2C19 genotype sub-groups, the impact of Duodenal Ulcer (DU) on utility value and drug-related side-effect data were obtained from the literature. The total costs of medications were calculated to estimate the treatment costs based on current drug retail prices in China. Expert surveys were conducted when published data were not available. Probabilistic sensitivity analysis was performed to gauge the robustness of the results. RESULTS: Ilaprazole, when compared with omeprazole, achieved a better overall clinical efficacy. For the overall population, Ilaprazole achieved an incremental cost effectiveness ratio (ICER) of yen132 056 per QALY gained. This is less than the WHO recommended threshold of 3-times the average GDP per capita in China (2014). Furthermore, sub-group analysis showed that Ilaprazole is cost-effective in every province in CYP2C19 hetEM patients and in the most developed provinces in CYP2C19 homEM patients. Probabilistic sensitivity analysis suggests that the results are robust with 97% probability that ilaprozole is considered cost-effective when a threshold of 3-times China's average GDP per capita is considered. LIMITATION: This study didn't have the data of Ilaprazole combined with Hp eradication therapy. Caution should be taken when extrapolating these findings to DU patients with an Hp eradication therapy. CONCLUSIONS: The cost-effectiveness analysis results demonstrated that Ilaprazole would be considered a cost-effective therapy, compared with omeprazole, in Chinese DU patients based on the efficacy projections in various CYP2C19 polymorphism types.

A Randomized, Double-blind, Active-Controlled, Multi-center Study of Ilaprazole in the Treatment of Reflux Esophagitis.[Pubmed:27605258]

Clin Drug Investig. 2016 Dec;36(12):985-992.

BACKGROUND AND OBJECTIVE: Proton pump inhibitors (PPIs) are the main drugs for the treatment of reflux esophagitis. Previous studies have indicated Ilaprazole to be safer and more effective in treating duodenal ulcers as compared with omeprazole. Being a novel PPI, Ilaprazole may be used in the treatment of reflux esophagitis. The purpose of this study was to evaluate the safety and efficacy of Ilaprazole tablets in the treatment of reflux esophagitis. METHODS: This study used a randomized, double-blind, multi-center, active-comparison design. The patients were randomly divided into an Ilaprazole group (10 mg once daily and 15 mg once daily) and an esomeprazole group (40 mg once daily). Both the groups were treated for 8 weeks. Heartburn and reflux symptoms prior to treatment, and 4 and 8 weeks after the treatment were assessed. Gastroscopy was performed after 4 and 8 weeks. The healing rate after 4 weeks treatment was compared. If esophagitis was healed at the end of 4 weeks, patients did not undergo gastroscopy at the end of 8 weeks. RESULTS: Three hundred and twenty-five patients were enrolled in this study. The 4-week full analysis set (per-protocol set) healing rates in the esomeprazole 40-mg group, the Ilaprazole 10-mg group, and the Ilaprazole 15-mg group were: 71.43 % (78.89 %), 81.31 % (86.73 %), and 71.70 % (81.40 %), respectively, p = 0.1595 (0.4122); the 8-week healing rates were 84.76 % (93.33 %), 88.79 % (94.90 %), and 85.85 % (97.67 %), respectively, p = 0.6689 (0.4049). Drug-related adverse events rate were 10.48 %, 14.02 %, and 15.09 %, respectively, in the three groups (p = 0.6114). CONCLUSION: The efficacy and safety of Ilaprazole (10 mg/day, 15 mg/day) in treating reflux esophagitis was similar to esomeprazole (40 mg/day). Ilaprazole (10 mg/day) has a smaller dosage, hence it should be considered more in clinical uses. TRIAL REGISTRATION: ClinicalTrials.gov NCT01107938.

Ilaprazole for the treatment of gastro-esophageal reflux.[Pubmed:27598861]

Expert Opin Pharmacother. 2016 Oct;17(15):2107-13.

INTRODUCTION: Despite the undoubted benefit of proton pump inhibitors (PPIs), they have several shortcomings, such as a slow onset of action and a remarkable inter-individual variability, that limit the complete success of these drugs. Recently, a new PPI, Ilaprazole, has been developed and used in GERD patients. AREAS COVERED: The present review provides an update on the following points: current knowledge of GERD mechanisms; limitations of actual therapies; pharmacokinetic profile and metabolism of Ilaprazole; initial studies on the therapeutic efficacy of Ilaprazole in GERD. EXPERT OPINION: Compared with all other approved PPIs, Ilaprazole has shown an extended plasma half-life, a metabolism not significantly influenced by CYP2C19 genetic polymorphism and similar safety. This characteristics account for a low inter-individual variability, particularly in Asian populations, a higher suppression of gastric acid secretion, a more rapid acid control and consequent quicker symptom relief and a better effect on nocturnal acidity. However, clinical investigations assessing the efficacy of Ilaprazole in the management of GERD are lacking and therefore the potential improvements achievable with Ilaprazole in the current standard of care for acid-suppressing treatment must be confirmed in large and randomly controlled clinical trials enrolling patients with both erosive and non-erosive reflux disease.