Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations

Introduction: About 30–40% of GERD patients report an inadequate response to proton pump inhibitors (PPIs) due to their suboptimal pharmacological profiles. Recently, a new synthesized P-CABs, vonoprazan, showed higher suppression of gastric acid secretion as compared to lansoprazole.

Areas covered: This review provides an update on the pharmacokinetic properties of vonoprazan and their correlates with pharmacodynamics; preliminary data on the therapeutic efficacy of vonoprazan as compared to lansoprazole in GERD patients

Expert opinion: At variance from all available PPIs, vonoprazan acts directly on H+,K+-ATPase irrespectively of its activity, providing a fast onset of action without requiring acid activation and specific administration timing. Clinical and pharmacological investigations have confirmed a more rapid, potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a less antisecretory variability, as compared with PPIs. Preliminary data in patients with erosive esophagitis (EE) have shown the non-inferiority of vonoprazan to lansoprazole in terms of symptom relief and healing rate. Since these pharmacokinetic advantages, it is expected that it will have a significant favorable impact on GERD management. However, the clinical use of vonoprazan raises also some issues about its efficacy and safety in the long-term that deserve verification and careful investigation.     

Evolving pharmacological approaches in gastroesophageal reflux disease

Introduction: Proton pump inhibitors (PPIs) have considerably improved quality of life in patients with gastroesophageal reflux disease (GERD). However, many patients remain symptomatic despite standard PPI therapy.

Areas covered: This review focuses on evolving therapeutic strategies related to the pathophysiological processes of GERD and insufficient response to PPIs. Several clinical trials evaluated new PPI formulations and newer types of acid-suppressive drugs. These studies have evaluated traditional end points in GERD, but have not shown clinical superiority to current PPIs. Novel therapeutic strategies targeting underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxations (TLESRs) and esophageal hypersensitivity, are being developed for add-on therapy to PPIs. Prokinetic drugs may also have some potential in the add-on treatment of GERD with insufficient response to PPIs. Add-on studies are hampered by insufficient information on optimal patient selection and lack of established end points.

Expert opinion: Newer drugs for symptomatic control in GERD have largely focused on improved acid suppression, without evidence of clinical superiority. Drugs targeting esophageal motility and sensitivity to be used as add-onc therapy in PPI insufficient responders have not reached Phase III trials to date, due to difficulties with patient selection, tolerability and end points.     

A review of pharmacotherapy for treating gastroesophageal reflux disease (GERD)

Introduction: Medical therapy of gastroesophageal reflux disease (GERD) is based on the use of proton pump inhibitors (PPIs) as first choice treatment. Despite their effectiveness, about 20–30% of patients report an inadequate response and alternative drugs are required.

Areas covered: This review provides an overview of current pharmacotherapy for treating GERD by showing the results of PPIs, reflux inhibitors, antidepressants and mucosa protective medications.

Expert opinion: Medical therapy of GERD does not definitely cure the disease, because even PPIs are not able to change the key factors responsible for it. However, they remain the mainstay of medical treatment, allowing us to alleviate symptoms, heal esophagitis and prevent complications in the majority of cases. Nevertheless, many patients do not respond, because acid does not play any pathogenetic role. Prokinetics and reflux inhibitors have the potential to control motor abnormalities, but the results of clinical trials are inconsistent. Antidepressant drugs are effective in specific subgroups of NERD patients with visceral hypersensitivity, but larger, controlled clinical studies are necessary. Protective drugs or medical devices have been recently adopted to reinforce mucosal resistance and preliminary trials have confirmed their efficacy either combined with or as add-on medication to PPIs in refractory patients.     

Evolving drugs in gastroesophageal reflux disease: pharmacologic treatment beyond proton pump inhibitors

Importance of the field: Despite the clinical success of proton pump inhibitors to treat gastroesophageal reflux disease (GERD), for the majority of patients in both gastroenterology and primary care clinics there is still a substantial group of patients (up to 40% in some studies) who do not completely respond symptomatically to a standard dose of proton pump inhibitors (PPIs). Specific explanations for these PPI noncomplete responders included transient lower esophageal sphincter relaxations (TLESRs), sensitivity to weakly acidic and/or alkaline reflux, large volume of reflux and esophageal hypersensitivity. There is a clear need for GERD therapies beyond the PPIs.

Areas covered in this review: These drug classes include the GABA_B receptor agonists (including lesogaberan and arbaclofen placarbil), mGluR5 receptor antagonists, P-CABs, cholecystokinin₂ antagonists and add-on therapies to PPIs including mosapride and rikkunshito.

What the reader will gain: Both physicians and patients are eagerly awaiting the development and FDA approval of a new class of anti-GERD medications targeting distinct mechanisms. This article provides information on pharmacologic strategies, clinical trials and side-effect profiles on several of the most promising and heavily researched compounds being developed today for the treatment of GERD symptoms and inflammation. Hopefully, this important research will help a large group of PPI noncomplete responding patients receive symptomatic relief and reduce esophageal inflammation through a unique pharmacologic mechanism in the near future.

Take home message: The treatment of GERD has greatly improved with the PPI class of therapy. Despite excellent success, there is a sizeable population of patients who do not have adequate response to therapies directed only at acid suppression. Emerging new pharmacologic treatment options show promise in further advancing the treatment success of GERD.     

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

Introduction: Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism.

Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy.

Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs.     

An update on the latest chemical therapies for reflux esophagitis in children

Introduction: Gastroesophageal reflux (GER), and its complicated form gastroesophageal reflux disease (GERD) is a common condition in infants and children. As GERD is often considered to cause extra-oesophageal symptoms in children and in the absence of standardized diagnostic and treatment algorithm, many children are inappropriately exposed to empirical anti-reflux treatments, with Acid-Suppressive Medications (ASM); mostly proton pump inhibitors (PPIs).

Areas covered: The authors summarize the pharmacological management of pediatric GERD and discuss the efficacy of PPIs as randomized controlled trials have failed to demonstrate their clinical efficacy in the pediatric population. They consider the controversies surrounding the use of PPIs in the pediatric population as increasing evidence suggests of, although controversially, an increased risk of adverse events such as infection of the respiratory or gastrointestinal tract. Esophagitis is a complication that has a significant impact on weight gain and growth, as well as on the quality of life, and in such case, the benefit of treatment largely outweighs the risk.

Expert opinion: Clinicians should reserve ASM use for infants and children with proven esophagitis and avoid their routine use in patients with merely symptoms of GER. Treatment need and options must be frequently re-evaluated to reduce the risks associated with ongoing therapy.     

The relationship among proton pump inhibitors,bone disease and fracture

Introduction: There is growing concern about a possible association between the use of proton pump inhibitors (PPIs) and the development of fragility fractures, most notably hip and vertebral fractures. As PPIs are widely used in clinical practice, this association is of paramount clinical importance.

Areas covered: The authors review the published papers analyzing the relationship between PPI use and the occurrence of fragility fractures. The authors also explore the data supporting possible mechanisms through which PPIs may increase the risk of fracture, including the effects of PPIs on calcium homeostasis, bone mineral density and direct effects of PPIs on bone metabolism.

Expert opinion: Overall, though multiple observational studies have demonstrated an association between PPIs and fragility fractures, the lack of a proven mechanism through which PPIs increase the risk of fracture suggests that this association may not be causal. At this time, the authors do not recommend discontinuing PPIs in patients with a history of fracture or those at increased risk of fracture. However, clinicians should still endeavor to avoid using PPIs in situations where benefits are minimal or clinical indications are lacking.     

Vonoprazan fumarate for the management of acid-related diseases

Introduction: 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.     

Timely confirmation of gastro-esophageal reflux disease via pH monitoring: estimating budget impact on managed care organizations*

ABSTRACT

Background: Current guidelines recommend the use of pH monitoring to confirm the diagnosis of acid reflux in patients with a normal endoscopy. This analysis evaluated the financial impact of pH monitoring with the wireless pH capsule on a managed care organization (MCO) in the United States.

Methods: A decision model was constructed to project total 1-year costs to manage GERD symptoms with and without the adoption of wireless pH capsules in a hypo­thetical MCO with 10?000 eligible adult enrollees, of whom 600 presented with GERD-like symptoms. Costs of GERD diagnosis, treatment, and symptom management for those in whom a GERD diagnosis was ruled out by pH monitor­ing were assessed. The incremental per-member-per-month (PMPM) and per-treated-member-per-month (PTMPM) costs were the primary outcomes. Data sources included literature, expert input, and standardized fee schedules.

Results: An increase of 10 percentage points in the use of pH monitoring with wireless pH capsules yielded incremental PMPM and PTMPM costs of $0.029 and $0.481, respectively. The costs of proton pump inhibitor (PPI) therapy to the plan dropped to $236?363 from $238?086, while increases were observed in pH monitor­ing (from $16?739 to $21?973) and non-GERD therapy costs (from $1392 to $1740). The results were sensitive to the percentage of patients requiring repeat endoscopy before wireless pH monitoring and the cost of PPIs.

Conclusions: Timely and increased use of pH monitor­ing as recommended in published guidelines leads to less unnecessary use of PPIs with a modest budgetary impact on health plans.     

The role of the new basal insulin analogs in addressing unmet clinical needs in people with type 1 and type 2 diabetes

Background: Despite improvements in anti-hyperglycemic therapies, there are many unmet clinical needs that hinder successful glycemic control in people being treated with current basal insulin analogs.

Objective: This paper reviews the unmet needs associated with current basal insulin therapy and describes the most recent basal insulins for the treatment of diabetes.

Methods: PubMed was searched for articles on basal insulin analogs published between 2000 and April 2016.

Results: Although long-acting insulin analogs, such as insulin glargine 100 units/mL and insulin detemir, have come towards approximating physiologic basal insulin levels, limitations such as hypoglycemia and intra- and inter-individual variability are associated with their use resulting in glycemic fluctuations. Some basal insulins lack 24?hour coverage, requiring some patients to split their dose, increasing the number of injections required to maintain glycemic control. Fear of hypoglycemia and the need for additional injections often leads to poor compliance and suboptimal glycemic control. Long-acting insulin analogs, such as insulin glargine 300 units/mL and insulin degludec, have improved upon the shortcomings of the current basal insulin analogs. Improved pharmacodynamic/pharmacokinetic profiles afford lower intra-patient variability and an extended duration of action, providing full and stable 24?hour basal insulin coverage with once daily dosing, and comparable efficacy to insulin glargine with lower rates of hypoglycemia.

Conclusion: The improved pharmacodynamic/pharmacokinetic profiles of new long-acting insulin formulations provide greater glycemic control with once daily dosing. With the growing number of therapeutic choices available, physicians have more scope to individualize patient options for basal insulin therapy.     

Comment and reply on: Evaluation of injection force of three insulin delivery pens

Importance of the field: The use of clopidogrel and aspirin has become standard therapy in patients with acute coronary syndromes and stent implantation. However, concern arises because about 25% of subjects are nonresponders to clopidogrel. This nonresponsiveness is associated with a threefold increase in adverse outcomes. Clopidogrel resistance is multifactorial, but genetic polymorphisms in clopidogrel's metabolic activation (e.g., cytochrome P450 2C19) and drug–drug interactions at this level (e.g., between proton pump inhibitors (PPIs) and clopidogrel) are both associated with decreased clopidogrel efficacy. Despite all PPIs being potent inhibitors of CYP2C19, evidence about their clinical impact is controversial.

Areas covered in this review: Pharmacogenomic and pharmacokinetic aspects of clopidogrel nonresponsiveness were considered in detail.

What the reader will gain: The reader will gain an exhaustive review of the current state of the controversial issues regarding genetic polymorphisms and drug–drug interactions affecting clopidogrel efficacy.

Take home message: It is important to consider clopidogrel resistance in some patients and establish strategies to handle this problem (e.g., genotyping, platelet aggregability tests, new antiplatelet drugs). The combined use of PPIs and clopidogrel is at present regulated by the FDA and EMEA; however, the risk/benefit balance should be made for each patient individually.     

Evolving pharmacological approaches in gastroesophageal reflux disease

Introduction: Proton pump inhibitors (PPIs) have considerably improved quality of life in patients with gastroesophageal reflux disease (GERD). However, many patients remain symptomatic despite standard PPI therapy. Areas covered: This review focuses on evolving therapeutic strategies related to the pathophysiological processes of GERD and insufficient response to PPIs. Several clinical trials evaluated new PPI formulations and newer types of acid-suppressive drugs. These studies have evaluated traditional end points in GERD, but have not shown clinical superiority to current PPIs. Novel therapeutic strategies targeting underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxations (TLESRs) and esophageal hypersensitivity, are being developed for add-on therapy to PPIs. Prokinetic drugs may also have some potential in the add-on treatment of GERD with insufficient response to PPIs. Add-on studies are hampered by insufficient information on optimal patient selection and lack of established end points. Expert opinion: Newer drugs for symptomatic control in GERD have largely focused on improved acid suppression, without evidence of clinical superiority. Drugs targeting esophageal motility and sensitivity to be used as add-onc therapy in PPI insufficient responders have not reached Phase III trials to date, due to difficulties with patient selection, tolerability and end points.     

Predictors of heartburn resolution and erosive esophagitis in patients with GERD

ABSTRACT

Objectives: The primary objective was to assess gastroesophageal reflux disease (GERD) symptom resolution rates with esomeprazole by erosive esophagitis (EE) status, and the secondary objective was to evaluate potential predictors of the presence of EE and heartburn resolution.

Background: Patients with GERD who have EE have higher reported symptom resolution rates than those with nonerosive reflux disease (NERD) when treated with proton pump inhibitors (PPIs).

Study: This open-label multicenter study included adults with GERD symptoms. Patients were stratified by EE status after endoscopy and received once-daily esomeprazole 40?mg for 4 weeks. Questionnaires determined symptom response rates, and baseline predictors of EE or heartburn resolution were evaluated. Potential predictors, including years with GERD, history of EE, and time to relief with antacids, were examined.

Results: Heartburn resolution rates at 4 weeks were higher for patients with EE than NERD (69% [124/179] vs. 48% [85/177]; p?<?0.0001). Multivariate models had moderate predictive ability for EE (c-index, 0.76) and poor predictive ability (c-index, 0.57) for heartburn resolution. However, faster heartburn relief with antacid use, particularly within 15?min, was predictive of EE and heartburn resolution.

Conclusions: Patients with EE have higher heartburn resolution rates than patients with NERD after treatment, although recall bias may be possible. Fast relief with antacid use is predictive of EE and heartburn resolution with a PPI and suggests that a history of antacid relief may provide corroborative evidence to empiric PPI therapy in determining whether patients with heartburn have acid reflux disease.

Trial registration: ClinicalTrials.gov identifier: NCT00242736.     

Proton pump inhibitors: use and misuse in the clinical setting

ABSTRACT

Introduction: The introduction of proton pump inhibitors (PPIs) into clinical practice has greatly improved our therapeutic approach to acid-related diseases for their efficacy and safety.

Areas Covered: The following evidence-based indications for PPI use are acknowledged by many scientific societies: treatment of the various forms and complications of gastroesophageal reflux disease, eradication of H. pylori infection in combination with two or more antibiotics, short- and long-term therapy of H. pylori-negative peptic ulcers, healing, and prevention of NSAID/COXIB-associated gastric ulcers, co-therapy with endoscopic procedures to control upper digestive bleeding and medical treatment of Zollinger Ellison syndrome.

Expert Commentary: Despite the above well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries and the endless expansion of the PPI market has created important problems for many regulatory authorities for two relevant features: the progressive increase of the costs of therapy and the greater potential harms for the patients. The major reasons for the misuse of PPIs are the prevention of gastro-duodenal ulcers in patients without risk factors and the stress ulcer prophylaxis in non-intensive care units, steroid therapy alone, anti-platelet or anti-coagulant treatment in patients without risk of gastric injury and the overtreatment of functional dyspepsia.     

Proton pump inhibitors in the treatment of gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GERD) is the most common peptic acid disease in the western world and is the commonest indication for acid suppression therapy. Major advances have been made over the past 30 years in the understanding of lower oesophageal sphincter function and the mechanism of acid secretion. Developments in surgical and pharmacological therapy have paralleled these advances. Pharmacotherapy for GERD has evolved from antacids to H₂-receptor antagonists (H₂RAs) to prokinetics to proton pump inhibitors (PPIs). The H₂RAs, while modestly effective in symptom relief and healing of GERD, are limited by pharmacological tolerance. The prokinetics (metoclopramide and cisapride) are limited by low efficacy, pharmacological tolerance and toxicity. The PPIs have emerged as the most effective therapy for symptom relief, healing and long-term maintenance. They have also proved to be remarkably safe and cost-effective in long-term therapy. This review evaluates the pharmacology, efficacy, tolerability, safety and cost-effectiveness of the four currently available PPIs, lansoprazole, omeprazole, pantoprazole and rabeprazole, in the treatment of GERD.     

2014—2016年成都25家医院质子泵抑制剂使用情况分析

目的 分析2014—2016年成都地区25家医院质子泵抑制剂（PPIs）的使用情况,为临床合理用药提供参考。方法 抽取成都地区25家医院2014—2016年PPIs的使用数据,对销售金额、用药频度（DDDs）、日均费用（DDC）和排序比（B/A）等进行回顾性分析。结果 2014—2016年成都地区25家医院PPIs的销售金额连续3年呈递减趋势,同时总DDDs先增加后减少,2016年呈现最低值。口服类PPIs以雷贝拉唑钠位居DDDs排名的第1位,注射类PPIs中以注射用泮托拉唑钠连续3年均稳居销售金额和DDDs排名的第1位。口服类PPIs中艾普拉唑的DDC最大,且同步性较好。注射类PPIs以艾司奥美拉唑的DDC最大,在同步性方面,泮托拉唑同步性最好。结论 通过加强合理用药监控手段,成都地区25家医院PPIs的使用量得到有效控制,使用日趋合理化。     

Discontinuation of proton pump inhibitors in patients on long-term therapy: a double-blind, placebo-controlled trial

BACKGROUND: The proportion of proton pump inhibitor users on long-term therapy who can discontinue proton pump inhibitor (PPI) medication without developing symptoms is unknown. AIM: To determine the proportion of patients on long-term PPI therapy who are able to discontinue PPIs without developing symptoms. METHODS: Patients on long-term PPIs, without a history of peptic ulcer or esophagitis underwent upper endoscopy. Patients were randomized double-blindly to taper down or continue a constant dosage of omeprazole for three weeks. Thereafter, all patients discontinued PPIs. RESULTS: Of the 97 patients enrolled, had used PPIs for 48 months, 78% had GERD. A total of 27% did not use PPIs during the year after discontinuation, 31% of the patients randomized to tapering discontinued PPIs and 22% of those who did not could discontinue therapy (NS). Gastro-oesophageal reflux disease (GERD) patients were more prone to continue PPIs than non-GERD patients. Only 16 (21%) of GERD patients were off PPIs vs. 48% of patients without GERD (p < 0.05). Serum gastrin was higher at baseline in GERD patients who resumed PPIs versus non-resumers (p < 0.05). GERD and serum gastrin were independent predictors of PPI requirement. CONCLUSIONS: Discontinuation of PPI was successful in 27% of long-term PPI users. GERD patients had more difficulty discontinuing PPIs than non-GERD patients.     

Nuclear receptors and drug metabolism for the personalization of cancer therapy

Introduction: A remarkable inter-individual variability in the occurrence of severe side effects represents an ongoing challenge in cancer treatment. Significant research efforts have focused on elucidating the contribution of the host genetic variability, but only a few markers have been identified for use in clinical practice. Several studies demonstrated that PXR and CAR activation can affect the expression of genes involved in absorption, distribution, metabolism and excretion (ADME) of antineoplastic drugs. The study of the host genetic background of Pregnane X Receptor (PXR; NR1I2) and Constitutive Androstane Receptor (CAR; NR1I3 and NR1I4), represents a new and attractive strategy to discern variability in ADME of antineoplastic drugs.

Areas covered: An update of the most important findings about investigational CAR and PXR pharmacogenetic markers of anti-cancer drugs toxicity is provided.

Expert opinion: A differential activation of PXR and CAR can affect the pharmacokinetics and pharmacodynamics of antineoplastic drugs. Pharmacogenetics studies published up to date provide encouraging even if exploratory results. Future large and prospective studies will clarify the clinical value of PXR and CAR genetic markers in treatment personalization.