Maintenance Of Erosive Esophagitis Research Articles

Review of the clinical development of fexuprazan for gastroesophageal reflux-related disease.

Proton pump inhibitors (PPIs) are a mainstay treatment for acid peptic disorders such as gastroesophageal reflux disease (GERD). Although PPIs are considered first-line medications for acid suppression, they have notable limitations such as requiring acid-mediated activation, short half-life and duration of action, and metabolic variability. Fexuprazan is a newly developed potassium-competitive acid blocker (P-CAB), which inhibits acid generation and secretion in a competitive and reversible manner. Fexuprazan, like other P-CABs, has significantly different pharmacodynamic and pharmacokinetic properties than PPIs with potential advantages including rapid, robust, and durable acid suppression, lack of CYP2C19 metabolism, independence from food intake, and no requirement for activation into an active form. Completed clinical trials of fexuprazan have demonstrated comparable efficacy to PPIs for the healing of erosive esophagitis and relief of GERD-related esophageal symptoms without concerning safety signals. Ongoing clinical trials are evaluating fexuprazan for the prevention of NSAID-induced peptic ulcer disease, non-erosive GERD, and acute and chronic gastritis, as well as healing efficacy and maintenance of erosive esophagitis (EE). Fexuprazan is approved in South Korea for the treatment of EE and at the time of this writing is being considered for regulatory approval in several other countries. In this article, we summarize and discuss the pharmacology, efficacy, and safety of fexuprazan.

S470 Development and Utilization of a Pharmacokinetic/Pharmacodynamic Model for Vonoprazan to Assess the Relationship Between Dose, Exposure, and pH Holding Time Ratio

Introduction: Vonoprazan, a potassium-competitive acid blocker, suppresses gastric acid secretion rapidly and potently over prolonged periods. Gastric acid suppression is key to the healing and maintenance of erosive esophagitis (EE) and the eradication of Helicobacter pylori infection. The daily fraction of time that gastric pH is >4 (the pH >4 holding time ratio [HTR]) is critical for healing of EE; pH >6 HTR is important for eradication of H. pylori infection. Here, we develop and utilize a pharmacokinetic (PK)/pharmacodynamic (PD) model to investigate the relationship between vonoprazan treatment and intragastric pH HTR. Methods: Data from prior Phase 1 single and multiple dose studies with pH measurements were pooled. An existing population PK model was used to estimate individual model parameters and predict PK profiles for study participants on each day with pH measurements. The area under the concentration-time curve between 0 and 24 hours post-dose (AUC0–24h) was merged with pH HTR PD study data. Three direct link PK/PD models characterizing the relationship between AUC0–24h and HTRs for pH >4, >5, and >6 were then derived. The models were used to simulate pH HTRs with between-subject variability; results were summarized as mean and 80% prediction intervals. Results: Data from 245 participants in five different Phase 1 studies were used to derive the PK/PD model. Demographics: 95.1% male; 50.6% Japanese; 49.4% Western. The estimates and 95% confidence intervals for all model parameters are shown in Table. Simulations showed that vonoprazan 20 mg once-daily (QD) and 20 mg twice-daily (BID) are predicted to give pH >4 HTRs of 89.7% and 98.1%, respectively, by Day 7 (Figure). HTRs for pH >6 were 53.1% for vonoprazan 20 mg QD and 75.3% for BID. Conclusion: These results indicate that vonoprazan provides high, dose-dependent pH HTRs and, therefore, consistent, dose-dependent control of 24-hour intragastric acidity. These pH HTRs may explain the high EE healing rates and, when combined with antimicrobials, H. pylori eradication rates seen with vonoprazan in clinical trials.Figure 1.: Predicted Mean and 80% Prediction Interval pH Holding Time Ratio at Days 0 (pre-treatment), 1, 7 and 14. BID, twice daily; QD, once daily. Table 1. - Estimates and 95% CIs for Model Parameters Parameter Role pH >4 Estimate (95% CI) pH >5 Estimate (95% CI) pH >6 Estimate (95% CI) E0 TV (logit) -2.74 (3.77%)(-2.84 to -2.64) -3.18 (1.56%)(-3.27 to -3.09) -3.48 (0.514%)(-3.54 to -3.42) Asian-effect (%) -12.8 (-17.3 to -8.41) -9.23 (-12.7 to -5.74) -5.63 (-8.11 to -3.15) BSV 0.388 (0.310 to 0.465) 0.276 (0.192 to 0.361) 3.16e-05 (-0.286 to 0.286) EC50 TV (ng/mL) 48.2 (43.9 to 52.4) 58.8 (53.1 to 64.5) 99.5 (86.2 to 113) gamma 1.39 (1.20 to 1.58) 1.34 (1.17 to 1.52) 1.62 (1.30 to 1.94) Weight effect (1/kg) 1.50 (0.803 to 2.19) 1.81 (1.19 to 2.44) - BSV 0.319 (0.259 to 0.379) 0.310 (0.252 to 0.368) 0.235 (0.102 to 0.368) Emax TV (logit) 4.80 (102%)(4.53 to 5.07) 4.83 (102%)(4.44 to 5.23) 2.17 (91.9%)(1.65 to 2.70) Weight effect (1/kg) - - -0.0187 (-0.0265 to -0.0108) BSV 1e-04 (6.80e-05 to 0.000132) 1e-04 (5.42e-05 to 0.000146) 0.781 (0.505 to 1.06) ET50 TV (days) 0.432 (0.384 to 0.481) 0.427 (0.369 to 0.485) 0.348 (0.274 to 0.422) delta 1 (fixed) 1 (fixed) 1 (fixed) RUV add.err. (logit) 0.528 (0.475 to 0.580) 0.545 (0.493 to 0.596) 0.498 (0.457 to 0.539) E0 and Emax were estimated on the logit-scale as the pH holding time ratios were logit-transformed; back-transformed estimates on the original percent scale are given for these parameters in round brackets. add.err., additive error; BSV, between subject variability; CI, confidence interval; E0, baseline effect; Emax, theoretical maximum effect achieved at infinite exposure and time; EC50, exposure (AUC) required to achieve 50% of maximum effect (Emax); ET50, time required to achieve 50% of maximum effect; RUV, residual unexplained variability; TV, typical value.

A novel rp-hplc method for determination of esomeprazole in pharmaceutical dosage forms in human plasma: A pilot stress degradation study

Esomeprazole, an proton pump inhibitor used for the remedy of acid reflux disorders including healing and maintenance of erosive esophagitis, gastroesophageal reflux disease and peptic ulcer disease. It is utilized in a prolonged treatment of pathological hypersecretory conditions such as Zollinger -Ellison syndrome. In this study, a novel RP-HPLC method was developed for the determination of esomeprazole both in API and tablets (Esmoz (40mg)), Phenomenex Luna, 5μm C18 100 A° LC column (250X4.6mm) was used at 40°C. Isocratic elution was utilized with acetonitrile: water (96:4v/v) mixture. The flow rate was 1.0mL min-1 and UV detection was at 270nm. The RT value was observed at 3.713 minutes respectively. The developed method was validated according to ICH guidelines and found to be linear within the range of 100-500μg/mL. In similar lines, linearity was achieved by spiking esomeprazole in human plasma within the range of 20-80μg/mL. The developed method was accurate, precise, robust, and rapid. Hence it can be applied for both stability studies and routine quality control analyses.

Dexlansoprazole: delayed-release orally disintegrating tablets for the treatment of heartburn associated with non-erosive gastroesophageal reflux disease and the maintenance of erosive esophagitis

ABSTRACTIntroduction: Gastroesophageal reflux disease (GERD) is a common condition afflicting millions of patients, whose prevalence continues to rise owing to the aging population and increasing burden of comorbid conditions, such as obesity. Currently, the mainstay of therapy for GERD is treatment with proton pump inhibitors (PPIs), which have proven efficacy, safety, and tolerability. Despite this, a considerable number of patients have refractory symptoms to PPI therapy. Dexlansoprazole is a new addition to the class of PPIs, which has a unique dual delayed drug release system, which aims to address the current limitations of acid suppressive therapy by offering extended acid suppression and improved ease of administration.Areas covered: This manuscript covers the pharmacokinetics, pharmacodynamics, clinical efficacy, and regulatory approval of dexlansoprazole. Additionally, there is further discussion concerning the current market settings and the potential future impact of dexlansoprazole.Expert commentary: Overall, dexlansoprazole offers benefits in its ease of administration and proven efficacy in the healing, maintenance of erosive esophagitis, and symptomatic non-erosive GERD. Long-term, dexlansoprazole will likely find a niche market among patients who fail other acid suppressive therapy or who desire simplified administration for compliance concerns, but will likely come at a higher out of pocket expense than comparable generic PPIs.

Proton pump inhibitors for the treatment of patients with erosive esophagitis and gastroesophageal reflux disease: current evidence and safety of dexlansoprazole.

Gastroesophageal reflux disease is the most common upper gastroenterology disorder in the US. It is associated with a variety of complications and significantly impacts quality of life. Proton pump inhibitors are the most effective treatment. Dexlansoprazole modified release (MR) is a proton pump inhibitor that employs a novel release formulation that prolongs its absorption and allows for more flexibility in dosing. Dexlansoprazole MR can be dosed without regard to food intake or time of day, and once-daily dosing may replace twice-daily dosing of other agents. Dexlansoprazole MR is effective for healing and maintenance of erosive esophagitis, and for the treatment of nonerosive disease, including nocturnal gastroesophageal reflux disease. Dexlansoprazole MR is safe and well tolerated, and can improve quality of life.

Dexlansoprazole Delayed Release: Pharmacotherapy of Erosive Esophagitis and GERD

Dexlansoprazole MR is a modified release formulation of the R-enantiomer of lansoprazole, which employs a novel Dual Delayed Release (DDR) technology. Pharmacokinetic studies have shown that the DDR technology provides a two peaks drug release, accuring 1–2 hours and 4–5 hours after dosing, leading to an extended duration of therapeutic plasma drug concentrations compared with conventional delayed release lansoprazole. Dexlansoprazole MR 30 and 60 mg provided superior intragastric pH control compared to that obtained with lansoprazole 15 mg and 30 mg once daily dosing. Dexlansoprazole can be taken without regard to food. The drug has been shown to be as efficacious as lansoprazole in healing, and superior to placebo in maintaining healing, of erosive esophagitis. Dexlansoprazole appears to be well tolerated with a comparable safety profile to lansoprazole. Overall, dexlansoprazole DR has an interesting pharmacokinetic profile and is effective and well tolerated in the healing and maintenance of erosive esophagitis and in the treatment of GERD. Nevertheless in the absence of head-to-head comparison there is no mean to recommend its use preferentially to other PPIs.

The evolution of proton pump inhibitors for the treatment of gastroesophageal reflux disease

This article reviews the diagnosis and current treatment options for gastroesophageal reflux disease (GERD) available to nurse practitioners, with a focus on advances in proton pump inhibitor (PPI) therapy. Review of scientific literature and clinical management guidelines for GERD treatment and PPI therapy from the PubMed database, Google Scholar, and other World Wide Web resources. A number of safe and effective treatment options exist for GERD. Recent developments in PPI technology may begin to address unmet needs in PPI therapy. GERD is commonly diagnosed and treated by nurse practitioners in the primary care setting. Acid suppression therapy is the primary medical therapy for GERD. PPI therapy provides symptomatic relief of heartburn and regurgitation, as well as effective healing and maintenance of erosive esophagitis. Newer PPIs lengthen the duration of acid suppression and allow for more flexibility in dosing, which may improve medication adherence and decrease episodes of acid breakthrough.

Dexlansoprazole: A proton pump inhibitor with a dual delayed-release system

Background: Dexlansoprazole, the dextrorotatory enantiomer of lansoprazole, is a proton pump inhibitor (PPI) formulated to have dual delayed-release properties. It is indicated for healing all grades of esophagitis, maintaining the healing of erosive esophagitis (EE), and treating heartburn associated with nonerosive gastroesophageal reflux disease. Objective: This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of dexlansoprazole, as well as its clinical efficacy and tolerability. Methods: MEDLINE (1966–April 2010) and International Pharmaceutical Abstracts (1970–April 2010) were searched for original research and review articles published in English using the terms dexlansoprazole and TAK-390MR. The reference lists of identified articles were reviewed for additional pertinent publications. Abstracts from 2007–2009 American College of Gastroenterology and Digestive Disease Week meetings were searched using the same terms. Results: By irreversibly binding to H +K +-ATPase, dexlansoprazole inhibits acid production by the parietal cell. Its dual delayed-release formulation provides 2 distinct releases of medication, prolonging the mean residence time compared with lansoprazole (5.56–6.43 vs 2.83–3.23 hours, respectively). In 2 identical Phase III trials of the healing of EE, there were no significant differences in rates of complete healing after 8 weeks between dexlansoprazole 60 and 90 mg once daily and lansoprazole 30 mg once daily. In 2 studies of the maintenance of healing of EE, rates of healing at 6 months were significantly higher with dexlansoprazole 30, 60, and 90 mg once daily compared with placebo ( P < 0.001). Patients with nonerosive reflux disease who received dexlansoprazole 30 or 60 mg once daily had significantly more 24-hour heartburn-free days compared with those who received placebo ( P < 0.001). Dexlansoprazole was well tolerated compared with placebo or lansoprazole in all studies. Conclusions: In the studies reviewed, dexlansoprazole was well tolerated and effective in the healing and maintenance of EE, and in the treatment of nonerosive reflux disease. However, most of the available evidence involved comparisons with placebo, making it difficult to draw meaningful conclusions about the place of dexlansoprazole among PPIs. More head-to-head comparative trials with other PPIs are needed to determine whether the unique formulation of dexlansoprazole translates into a clinically meaningful improvement in outcomes.