Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
Review
1.
Introduction
2.
Dexlansoprazole MR
3.
Esomeprazole strontium
4.
Conclusion
5.
Expert opinion
Treatment of gastroesophageal reflux disease: two new oral formulations dexlansoprazole MR and esomezol (esomeprazole strontium) Parth J Parekh, Edward C Oldfield IV & David A Johnson† †
Eastern Virginia Medical School, Gastroenterology Division, Department of Internal Medicine, Norfolk, VA, USA
Introduction: The prevalence of gastroesophageal reflux disease continues to increase with the aging population and the obesity epidemic. Therapeutic failures can have significant detrimental effects in patients. Recently, dexlansoprazole MR and esomeprazole strontium were introduced to the class of proton pump inhibitors (PPIs). Areas covered: This article will review the pharmacodynamics and pharmacokinetics of dexlansoprazole MR and esomeprazole strontium. Using the keywords ‘dexlansoprazole MR’ and ‘esomeprazole strontium’ in the search engines of PubMed, Cochrane Reviews and Google, we were able to identify peer-reviewed publications, abstracts and presentations at national society educations meetings and present a balanced view of the available data. Expert opinion: Dexlansoprazole MR and esomeprazole strontium offer an innovative delivery mechanism compared to conventional PPIs. Further trials are necessary in order to establish superiority. Keywords: dexlansoprazole MR, esomeprazole strontium, gastroesophageal reflux disease, proton pump inhibitors Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Gastroesophageal reflux disease (GERD) currently affects 20 -- 40 million people in the USA, the prevalence of which continues to increase with the aging population and the obesity epidemic [1,2]. Proton pump inhibitors (PPIs) are widely recognized as being superior to other antisecretory therapies, and thus have become the cornerstone of pharmacological therapy for the treatment of GERD [3]. Despite their established benefits, there are several factors implicated in PPI treatment failure as outlined in Table 1, most notably visceral hypersensitivity, which may be attributed to the non-esophageal reflux disease (NERD) phenotype, compliance and suboptimal pH control [4]. Recent advances in the medical management of GERD attempt to target the latter two limitations of PPI therapy. Although little is understood about the NERD phenotype, the most recent data suggest that those with NERD display variability in their response to PPI therapy but ultimately do not carry the downstream complications of treatment failure as do those with GERD [5]. Treatment failure in patients with GERD can result in the emergence of erosive esophagitis and its complications such as strictures, bleeding and the development of Barrett’s esophagus with or without dysplasia [6]. Dexlansoprazole MR and esomeprazole strontium are the newest PPI options and these may be of benefit to certain patient populations. This article will review the most current literature 10.1517/14656566.2014.911841 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
P. J. Parekh et al.
Article highlights. .
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
.
.
.
.
Dexlansoprazole MR offers a new innovative delivery mechanism where the initial drug release is in the proximal small intestine with subsequent release in various regions of the distal small intestine several hours later. Recent clinical trials have demonstrated dexlansoprazole MR to be as efficacious as other proton pump inhibitors (PPIs). The key advance in technology with the dual delay release formulation offers a twice-daily dosing effect in a one-time dose that may potentially enhance compliance or patient preference in the subset of patients who require twice-daily dosing. Esomeprazole strontium is an incrementally modified drug of esomeprazole magnesium using strontium salts rather than magnesium salts. Esomeprazole strontium is clinically identical to esomeprazole magnesium; however, at this time, there is insufficient clinical data comparing esomeprazole strontium with esomeprazole magnesium to draw a definite conclusion. Further clinical trials are necessary for both dexlansoprazole MR and esomeprazole strontium to prove superiority over the current available PPIs.
This box summarizes key points contained in the article.
Table 1. Cases of proton pump inhibitor therapy failure. Reason
Clinical implication
Compliance Helicobacter pylori
High Low -- no dose adjustment necessary Low -- no dose adjustment necessary; response rates among PPIs usually comparable Low Low Unclear High High -- may be as a result of NERD phenotype
Bioavailability
Nocturnal acid breakthrough Rapid metabolism/resistance NERD Delayed gastric emptying Visceral hypersensitivity
Data taken from [4]. NERD: Non-erosive reflux disease.
evaluating the pharmacodynamics and pharmacokinetics of dexlansoprazole MR and esomeprazole strontium. Additionally, a brief review of safety and efficacy from published clinical trials is provided. 2.
Dexlansoprazole MR
The most recent consensus guidelines addressed the discordance in the use of twice-daily PPI therapy typically used in clinical arena that is not typically addressed in clinical trial 2
data, despite the pharmacodynamics supporting twice-daily dosing [6-8]. Experts typically recommend the use of twicedaily PPI therapy to provide symptomatic relief in patients who have incomplete resolution of GERD-related symptoms to once-daily dosing. The advent of dexlansoprazole MR (Takeda Pharmaceuticals, Osaka, Japan) employs a novel approach by which its dual delayed release (DDR) formulation prolongs the plasma concentration ultimately extending the duration of acid suppression [8]. Pharmacokinetics and pharmacodynamics Dexlansoprazole MR is the R-enantiomer of the racemate lansoprazole, which selectively inhibits H+/K+ ATPase enzyme of gastric parietal cells resulting in suppression of acid secretion [9]. Following administration of lansoprazole, dexlansoprazole is the predominant circulating enantiomer accounting for approximately 80% of active metabolites of lansoprazole [10]. Dexlansoprazole MR utilizes DDR technology, which differs from conventional PPI delivery systems employing either immediate or delayed single-release formulations [11]. The DDR technology allows for an initial drug release in the proximal small intestine with subsequent release in various regions of the distal small intestine several hours later, resulting in a dual-peaked profile as compared to the single peak seen with conventional single-release PPIs. Higher doses of dexlansoprazole MR are required in order to maintain prolonged plasma concentrations and increased intragastric pH over a 24-h period. Metz et al. found the mean AUC and Cmax for dexlansoprazole MR (60, 90 and 120 mg) to be 3 -- 7 and 1.5 -- 3 times higher than compared to lansoprazole, respectively [10]. 2.1
Indications and usages Current manufacturer recommendations for dexlansoprazole in the adult population are for the treatment of healing all grades of erosive esophagitis (60 mg daily for 8 weeks), healing of erosive esophagitis (30 mg daily for up to 6 months), relief of reflux symptoms and the reflux associated with symptomatic non-erosive GERD (30 mg daily for 4 weeks) [11]. Dexlansoprazole can be taken with or without food, as there is no alteration of the bioavailability -- clearly there is a difference from all other PPIs [12]. Some patients, however, are more likely to have resolution of symptoms if taking therapy approximately 30 -- 60 min prior to a meal. 2.2
Safety and adverse effects In the clinical trials, the most commonly reported adverse effects of dexlansoprazole therapy were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%) and flatulence (1.6%) [6,13-16] As a whole, PPI therapy has been implicated with an increased risk of Clostridium difficile-associated diarrhea [17] and hypomagnesaemia [18] with prolonged treatment albeit rare. 2.3
Expert Opin. Pharmacother. (2014) 15(9)
Treatment of GERD
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
2.4
Clinical trials
A recent double-blind, randomized trial (performed at two different academic centers) evaluated the efficacy and safety of dexlansoprazole MR in healing erosive esophagitis [6]. Sharma et al. randomized 4092 patients to receive either dexlansoprazole MR (60 or 90 mg) or lansoprazole (30 mg) once daily, with primary endpoint assessing for healing using a closed testing procedure at week 8. They found that 92 -- 95% of patients were healed using dexlansoprazole MR versus 86 -- 92% of patients using lansoprazole; however, the differences were not statistically significant (p > 0.025). Crude rate analysis proved dexlansoprazole MR (90 mg) to be superior to lansoprazole in both studies, and the 60 mg formulation to be superior to lansoprazole in one study. An integrated analysis of 8-week healing in patients with moderate--severe erosive esophagitis yielded dexlansoprazole MR (90 mg) superior to lansoprazole, which led the authors to conclude dexlansoprazole MR effective in healing erosive esophagitis with benefits over lansoprazole, particularly in patients suffering from moderate to severe disease. Metz et al. sought to assess the efficacy and safety of dexlansoprazole MR in maintaining healed erosive esophagitis and symptomatic relief [19]. This double-blind trial randomized 445 patients with healed erosive esophagitis to receive dexlansoprazole MR (30 or 60 mg once daily) or placebo once daily for 6 months, with a primary endpoint of maintained endoscopic healing and secondary endpoints of continued symptom relief. They found maintenance rates in patients who received dexlansoprazole MR 30 mg, 60 mg and placebo to be 75, 83 and 27%, respectively, and that dexlansoprazole controlled heartburn (median of 91 -- 96% for 24-h heartburn-free days, 96 -- 99% for heartburn-free nights, which led to the conclusion that dexlansoprazole MR is efficacious in maintaining erosive esophagitis and providing symptomatic relief with a majority of patients being heartburn free for > 90% of days. Lastly, Fass et al. sought to evaluate the effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD [14]. They randomized 305 patients with moderate to very severe nocturnal heartburn and associated sleep disturbances to dexlansoprazole MR 30 mg or placebo once daily for 4 weeks. Patients who received dexlansoprazole MR were significantly less likely to experience nocturnal symptoms and associated sleep disturbances as compared to their placebo counterpart. The median percentage of nights without heartburn was 73.1% in the dexlansoprazole MR group compared to 35.7% in the placebo group (p < 0.001). In addition, dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of GERD-related sleep disturbances and nocturnal heartburn (69.7 vs 47.9% and 47.5 vs 19.6%, respectively; p < 0.001), which led the authors to conclude dexlansoprazole MR to be significantly more efficacious than placebo in reducing GERD-related sleep disturbances and symptomatic relief from nocturnal heartburn.
Bottom line: Currently, there is limited clinical data evaluating the efficacy of dexlansoprazole MR compared to conventional PPI therapy. The available data suggest that the higher doses of dexlansoprazole MR utilized in clinical trials are superior to traditional lansoprazole although there are no comparative trials to other PPIs. The key advance in technology with the dual delay release formulation offers a twice-daily dosing effect in a one-time dose that may potentially enhance compliance or patient preference in the subset of patients who require twice-daily dosing. Additionally, the lack of bioavailability effect when given with food may have a unique advantage for some patients where there are problems in compliance with the traditional instructions to take these medications 30 -- 60 min before breakfast. 3.
Esomeprazole strontium
In October 2010, Hanmi Pharmaceuticals (Seoul, South Korea) submitted a new drug application to the FDA for the approval of esomeprazole strontium, an incrementally modified drug of esomeprazole magnesium (Nexium) using strontium salts rather than magnesium (Mg) salts [20]. On August 6, 2013, the FDA granted marketing authorization for esomeprazole strontium [21]. The product will be released by Hanmi’s US marketing partner, Amneal Pharmaceutical (Bridegewater, NJ, USA) [22]. The FDA submission and drug approval does not provide specific clinical studies for esomeprazole strontium; rather, the extensive documentation of clinical studies for esomeprazole magnesium is cited in its place [23]. Esomeprazole is thermally unstable by itself and a stable crystalline form is needed to provide a pure and clinically useful dosage formulation. The crystalline formulation, esomeprazole magnesium (Nexium), was developed and ultimately commercially released in 2000. More recently, esomeprazole strontium was developed using strontium to provide a new crystalline salt for esomeprazole. Strontium is a trace metal in the human body that is a member of the same group of elements as Mg. In this respect they share many of the same chemical properties. Strontium has a mean bioavailability of about 20% with one study showing variations between 25% without a meal and 19% with a meal [24]. This is similar to the bioavailability of Mg with bioavailability around 24% under normal physiologic conditions [25]. The use of a strontium salt makes esomeprazole strontium a pharmaceutical alternative, which by definition from the FDA means ‘a drug product that contains the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester’ [26]. Esomeprazole strontium and esomeprazole magnesium are also said to be bioequivalent, which according to the FDA definition means the absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action when administered at the same molar
Expert Opin. Pharmacother. (2014) 15(9)
3
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
P. J. Parekh et al.
dose under similar conditions in an appropriately designed study. Bioequivalence was shown with 49.3 mg esomeprazole strontium achieving Cmax at approximately 1.7 h compared to 1.6 h for esomeprazole magnesium 40 mg. Additionally, the AUC that measures the mean exposure to esomeprazole was shown to be similar between the two formulations, which remained the case under both fasting conditions and also after 5 days of consecutive dosing [27]. The bioequivalence of esomeprazole strontium and esomeprazole magnesium has also reportedly been studied in a number of clinical trials; however, a search of available literature in the PubMed, Clinical Key and Science Direct databases as well as a search of clinical trials listed in ClinicalTrials.gov, the European Union Clinical Trials register and the South African National Clinical Trials Register fails to identify any studies on the topic [28]. Further evidence for the use of strontium in other pharmaceuticals is also based on its similarity to other elements in this same group as magnesium, in particular calcium (Ca), with which strontium shares a close resemblance. The similarity between strontium and Ca is close enough that it has been substituted for Ca in kinetic studies, in particular given its affinity for bone [29]. Elsewhere in the body, strontium and Ca compete for both intestinal absorption and renal tubular reabsorption; however, under normal physiologic conditions, the body is able to discriminate between the two elements. This similarity between these two elements has allowed for the development of strontium-containing compounds in the treatment of osteoporosis. Strontium ranelate has been shown to reduce the incidence of hip fractures and vertebral fractures in postmenopausal osteoporosis. The proposed mechanism relies on enhanced cell replication and bone formation via the activation of a Ca-sensing receptor thereby acting as an osteoblast agonist. The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee, however, has recently issued statement that strontium ranelate should no longer be used in the treatment of osteoporosis due to the increased risk for major adverse events [30]. These include 4 additional serious cardiac events and venous thromboembolism for every 1000 patient years and also an increased risk for serious skin reactions, disturbances in consciousness, seizures, liver inflammation and decreased number of red blood cells. The adverse effects of strontium, alone, do not reflect the same severity as those now identified for strontium ranelate; however, strontium’s close relationship with the activity of Ca may be the basis for some of the adverse effects of excess strontium. These adverse effects appear to be related to changes in the physiologic effects of Ca and vitamin D, more specifically the occurrence of rachitic lesions resulting from the impairment in intestinal absorption of Ca and renal production of 1, 25-dihydroxycholecalciferol [29]. Lastly, the risk of daily exposure to strontium appears minimal as animal models on the toxicity of strontium, with doses up to 40 mg/kg, showed only increased thyroid weight and increased levels of strontium in bone; however, no effects on bone were demonstrated [31]. 4
Pharmacokinetics and pharmacodynamics As there is currently only one study that includes a comparison between esomeprazole strontium to esomeprazole magnesium, much of the proposed difference in physiologic effect of esomeprazole strontium over other PPIs comes from the clinical trials of esomeprazole magnesium cited in the prescribing information [23]. Esomeprazole magnesium has been extensively studied, especially in comparison to its enantiomer, omeprazole. Some of the main differences between omeprazole and esomeprazole are related to differences in metabolism by the hepatic CYP enzymes, in particular CYP 2C19. Compared to omeprazole, esomeprazole is cleared more slowly than omeprazole, since it undergoes a less-extensive first-pass metabolism, and it also has minor CYP2C19 involvement, with 40% clearance for esomeprazole compared to 87% for omeprazole [32,33]. These two features translate into an enhanced bioavailability, increased specificity for the proton pump and increased inhibition of acid secretion due to a longer area under the plasma concentration--time curve [34,35]. Of note, esomeprazole does have some CYP 3A4 metabolism. In this respect, esomeprazole has the potential for increased drug--drug interactions, as CYP 3A4 is the major CYP enzyme responsible for 50% of drug metabolism [36]. Since the CYP enzymes extensively metabolize PPIs, in particular CYP 2C19, variations in the CYP 2C19 genotypes across populations can affect the metabolism and activity of PPIs. These differences have been shown with poor (PM) and intermediate metabolizers (IM) having both increased plasma levels of the active compound and acid inhibition as compared to the rapid metabolizers (RM) [37]. These polymorphisms, while most pronounced in East Asian populations, may still affect up to 30% of the white population [38]. The clinical significance of these polymorphisms on PPI function was recently addressed in a Japanese study that analyzed the CYP219 genotypes of 40 Helicobacter pylori negative volunteers and compared the median pH values between treatment with esomeprazole, omeprazole, lansoprazole and rabeprazole in PM, IM and RM CYP2C19 metabolizers [39]. Results of the study revealed that the median intragastric pH was higher than 5.0 in all PMs and IMs independent of the PPI used; however, in the RM group, the median intragastric pH for esomeprazole was significantly higher at 5.4 compared to the other PPIs, all < 5.0. While the authors of this study did note that the results could not be extrapolated to western countries due to wide variability in the CYP genotypes, the results of this study do suggest that esomeprazole may have increased effectiveness when compared to other PPIs on the basis of less-extensive CYP2C19 metabolism. 3.1
Indications and usages [23] The current indications for esomeprazole strontium in the adult population include the treatment of GERD, risk reduction of NSAID-associated gastric ulcers, H. pylori eradication 3.2
Expert Opin. Pharmacother. (2014) 15(9)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
Treatment of GERD
to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions including Zollinger-Ellison syndrome. Esomeprazole strontium is available in 24.65 and 49.3 mg tablets, equivalent to esomeprazole magnesium 20 and 40 mg, respectively. Esomeprazole strontium will be available in two different preparation/routes of administration, oral and nasogastric tube. The oral delayed-release capsules should be swallowed whole or opened and mixed with applesauce; the granules should not be chewed or crushed. For nasogastric preparation, the capsule can be opened and intact granules emptied into a catheter-tipped syringe for delivery through nasogastric tube. Gastroesophageal reflux disease Esomeprazole strontium is indicated at a dose of 24.65 or 49.3 mg (20 and 40 mg esomeprazole equivalents) once daily for 4 -- 8 weeks for the healing of erosive esophagitis with an additional consideration of 4 -- 8 weeks of treatment for those who do not heal. For the maintenance of healing of erosive esophagitis, esomeprazole strontium is indicated once daily at a dose of 24.65 mg (20 mg esomeprazole equivalent). Symptomatic treatment of GERD with esomeprazole strontium is indicated at a dose of 24.65 mg (20 mg esomeprazole equivalent) once daily for up to 6 months. Of note, the controlled studies for the use of esomeprazole strontium on GERD did not extend beyond 6 months. 3.2.1
Risk reduction of NSAID-associated gastric ulcer Esomeprazole strontium is indicated for risk reduction of NSAID-associated gastric ulcers at a dose of 24.65 or 49.3 mg (20 and 40 mg esomeprazole dose equivalents) once daily for up to 6 months. Those considered high risk for NSAID-associated ulcers are those over 60 years of age and/or with a documented history of gastric ulcers. 3.2.2
H. pylori eradication Esomeprazole strontium has been studied in combination with amoxicillin and clarithromycin as triple therapy for the eradication of H. pylori. The 10-day triple therapy consists of esomeprazole strontium administered once daily at a dose of 49.3 mg (40 mg esomeprazole equivalent) in combination with twice-daily 1000 mg amoxicillin and 500 mg clarithromycin. 3.2.3
Pathologic hypersecretory conditions Esomeprazole strontium is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome, at a dose of 49.3 mg (40 mg esomeprazole equivalent) twice daily. The dosages were noted to vary by the individual patient with doses up to 240 mg daily being administered [23]. In conclusion, the indications for esomeprazole strontium are the same as those of esomeprazole magnesium, including 3.2.4
treatment of GERD, risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions, including Zollinger-Ellinson syndrome [27]. Safety and adverse events The FDA prescribing information for esomeprazole strontium cites the clinical studies of esomeprazole magnesium [23]. The most frequently occurring adverse events (occurring in > 1%) were headache, diarrhea, nausea, flatulence, abdominal pain, constipation and dry mouth. The same class effects of PPIs apply to esomeprazole strontium, which include an increased risk of C. difficile-associated diarrhea [17], and hypomagnesaemia [18]. Currently, there are no adequate well-controlled trials to assess the safety of esomeprazole strontium for use in the pregnant population. Rather, evidence for the safety of esomeprazole strontium in pregnant women comes from animal models comparing the effects of esomeprazole strontium versus esomeprazole magnesium. Comparison of the effects on embryo-fetal development from gestational day 6 through gestational day 20 at doses of 0, 14, 69 and 280 mg/kg/day (up to 57 times the maximum recommended human dose [MRHD]) showed no developmental toxicity at any dosage level of esomeprazole strontium or esomeprazole magnesium [40]. Next, using the same doses, the pre- and postnatal effects of esomeprazole strontium versus esomeprazole magnesium were compared from gestational day 6 through lactation day 21 [40]. At doses equal to or greater than 69 mg (16.8 times the MRHD), esomeprazole strontium and esomeprazole magnesium were equivalent for decreased survival, body weight and body weight gain and neurobehavioral or general developmental delays in the immediate post-weaning timeframe. Doses greater than 14 mg/kg/day (3.4 times the MRHD) were associated with decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity. If doses were increased to > 138 mg/kg/day (33.6 times the MRHD), physeal dysplasia in the femur was observed. Overall, there were no effects related directly to the strontium salt, rather the toxicity was attributable to the esomeprazole. Lastly, the researchers evaluated the comparative effects of esomeprazole strontium and esomeprazole magnesium on juvenile rats, postnatal days 7 -- 35 [40]. For doses of 70, 140 and 280 mg/kg/day, reduced survival, alterations in erythrocyte parameters, reduced mean body weights and food consumption, intestinal metaplasia of the glandular stomach and perivascular infiltrates of the lunges were noted. Similar to the prenatal and postnatal data, no adverse effects were directly attributable to the strontium salt, but attributable to the esomeprazole. Esomeprazole strontium has been labeled Pregnancy Category C as a result of these toxicology trials and the lack of any well-controlled studies in pregnant women [23]. 3.3
Expert Opin. Pharmacother. (2014) 15(9)
5
P. J. Parekh et al.
Clinical trials A search of currently published literature failed to identify any clinical studies comparing esomeprazole strontium and esomeprazole magnesium. There were, however, scientific abstracts available comparing esomeprazole strontium and esomeprazole magnesium. One Korean study from 2011 compared the effectiveness of various PPIs (esomeprazole magnesium and esomeprazole strontium, included) on the eradication of H. pylori [41]. Researchers enrolled patients to receive a 7-day treatment course with lansoprazole, rabeprazole, esomeprazole strontium or esomeprazole magnesium in addition to amoxicillin and clarithromycin. Urea breath test was performed 4 weeks later to assess therapy responsiveness. The overall eradication rate in the study was 70.9% (546/770) with esomeprazole magnesium achieving the highest response rate at 76% (225/297), while for esomeprazole strontium the eradication rate was 66.7% (96/144). Bottom line: Esomeprazole strontium is a new formulation of esomeprazole that uses a strontium salt to improve on the solubility of esomeprazole that is currently approved for the same indications as esomeprazole magnesium. Esomeprazole strontium should likely be clinically identical to esomeprazole magnesium (as implied by identical indications and product labeling); however, without data from head-to-head clinical comparisons it is impossible to draw a definite conclusion. There is nothing available, however, to suggest that this agent would have any superior clinical effects compared to the parent compound esomeprazole magnesium.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
3.4
4.
Conclusion
Dexlansoprazole MR represents a new PPI formulation that builds on isomeric purification by combining with a dual delay release formulation, which prolongs the plasma concentration and duration of acid suppression. The lack of food impairment for diminishing either the pharmacokinetic or pharmacodynamic effect is notable and may be discriminatory for optimizing compliance and acid inhibitory effect in selected patients. Clinical trials of dexlansoprazole MR at this time point to evidence that dexlansoprazole MR is similar in efficacy when compared to lansoprazole for the healing of erosive esophagitis [6], maintenance of erosive esophagitis [19] and the reduction of GERD-related nocturnal symptoms and associated sleep disturbances [14]. Its dual release formulation may potentially increase compliance rates in the subset of patients normally requiring twice-daily dosing; however, there is insufficient clinical data at this point to support this hypothesis. Esomeprazole strontium represents a new formulation of esomeprazole magnesium. At this time, there is insufficient clinical data comparing esomeprazole strontium with esomeprazole magnesium to draw a definite conclusion. Future clinical studies may serve to further elucidate any significant differences between the two formulations, including relative safety in human subjects and differences in efficacy for the treatment of indicated conditions. 6
5.
Expert opinion
This discussion of these two new pharmacologic agents for the treatment of GERD highlights some important issues facing effective healthcare delivery, namely adherence and cost. While many discussions are focused on the overuse of PPIs for patients with severe disease, adherence represents a significant barrier to therapeutic success. As discussed, there is a subset of patients considered as treatment failures, in particular those who did not respond to twice-daily PPI dosing and continue to experience disease sequelae. A recent review of 16,311 patients prescribed PPIs revealed that patients are less likely to adhere to treatment with twice-daily dosing [42]. Therefore, the ability to offer effective treatment with oncedaily dosing may prove to increase adherence rates among those requiring long-term therapy. Dexlansoprazole MR is one such agent whose innovative drug delivery system offers the pharmacokinetics of twice-daily dosing in a once-daily dose. Unfortunately, cost may preclude a majority of patients from benefitting from these new agents. Dexlansoprazole MR starts around $180 for a 30-day supply, although there is a pharmacy savings card available to cover up to $55 per month after the first $20 of co-pay [43,44]. By comparison, generic omeprazole is available for $10 for a 30-day supply [45]. This represents a significant cost difference when considering long-term therapy. This tradeoff represents an important consideration that providers must be aware of when discussing treatment options for patients. Esomeprazole strontium represents the first alternative formulation of esomeprazole approved for sale in the US market. A search of local prices on GoodRx.com revealed a starting price for a 30-day prescription of esomeprazole strontium 49.3 mg to be roughly $70 [46]. Using the same search parameters, a 30-day supply of esomeprazole magnesium 40 mg costs around $240, which can be combined with a savings card from AstraZeneca that offers to pay up to $50 after the customer pays the first $25 of the co-pay [47,48]. Given the emphasis on healthcare reform and cost savings, the significant cost difference between these formulations may prove to affect consumer choices. With Nexium’s patent expiring in May 2014, the market may see significant changes in the near future. As discussed, however, there is a lack of head-to-head clinical trials on esomeprazole strontium versus esomeprazole at this time and is an area requiring further clinical investigation.
Declaration of interest DA Johnson is on the Advisory Board for Centocor, MedScape, JWatch Gastroenterology and Given and is a Consultant for Pfizer, Medivo. He is on Speaker’s Bureau for Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Pharmacother. (2014) 15(9)
Treatment of GERD
Bibliography
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002;122:1500-11
2.
El-serag HB, Graham DY, Satia JA, et al. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol 2005;100(6):1243-50
3.
4.
5.
6.
..
7.
8.
9.
Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135(4):1383-91; 1391.e1-5 Fass R, Shapiro M, Dekel R, et al. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease–where next? Aliment Pharmacol Ther 2005;22(2):79-94 Hershcovici T, Fass R. Nonerosive Reflux Disease (NERD) - an update. J Neurogastroenterol Motil 2010;16(1):8-21 Sharma P, Shaheen NJ, Perez MC, et al. Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation–results from two randomized controlled studies. Aliment Pharmacol Ther 2009;29(7):731-41 Large randomized control trial comparing dexlansoprazole MR to traditional PPI therapy. Vakil N, Van zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101(8):1900-20
10.
11.
Vakily M, Zhang W, Wu J, et al. Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials. Curr Med Res Opin 2009;25(3):627-38
12.
Lee RD, Vakily M, Mulford D, et al. Clinical trial: the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor– evidence for dosing flexibility. Aliment Pharmacol Ther 2009;29(8):824-33
13.
Available from: http://www.dexilanthcp. com/dosing [Accessed 21 December 2013]
14.
Fass R, Johnson DA, Orr WC, et al. The effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD. Am J Gastroenterol 2011;106(3):421-31 Demonstrated efficacy of dexlansoprazole MR on GERD-related sleep disturbances.
..
15.
16.
Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-28 Gremse DA. Lansoprazole: pharmacokinetics, pharmacodynamics and clinical uses. Expert Opin Pharmacother 2001;2(10):1663-70
Metz DC, Vakily M, Dixit T, et al. Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy. Aliment Pharmacol Ther 2009;29(9):928-37
..
17.
Peura DA, Metz DC, Dabholkar AH, et al. Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience. Aliment Pharmacol Ther 2009;30(10):1010-21 Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther 2009;29(7):742-54 Demonstrated the safety and efficacy of dexlansoprazole MR. Tleyjeh IM, Bin abdulhak AA, Riaz M, et al. Association between proton pump inhibitor therapy and clostridium difficile Expert Opin. Pharmacother. (2014) 15(9)
infection: a contemporary systematic review and meta-analysis. PLoS One 2012;7(12):e50836 18.
Johnson DA, Oldfield EC. Reported side effects and complications of long-term proton pump inhibitor use: dissecting the evidence. Clin Gastroenterol Hepatol 2013;11(5):458-64
19.
Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther 2009;29(7):742-54
20.
Available from: http://www.hanmipharm. com/eng/release/board_read.asp? seq=549&board_id=7 [Accessed 16 February 2014]
21.
Available from: http://www.hanmipharm. com/eng/release/board_read.asp? seq=652&board_id=7 [Accessed 16 February 2014]
22.
Available from: http://www.amneal.com/ headlines/archive/ESGPR002_Eso_Generic_Release_FINAL [Accessed 16 February 2014]
23.
Available from: http://dailymed.nlm.nih. gov/dailymed/lookup.cfm? setid=61a5a84e-0194-4f11-91f883d7ac404932 [Accessed 16 February 2014] Provided manufacturer recommendations as well as pharmacokinetics and pharmacodynamics of esomeprazole strontium.
.
24.
Sips AJ, Van der vijgh WJ, Barto R, et al. Intestinal absorption of strontium chloride in healthy volunteers: pharmacokinetics and reproducibility. Br J Clin Pharmacol 1996;41(6):543-9
25.
Jahnen-Dechent W, Ketteler M. Magnesium basics. Clin Kidney J 2012;5(Suppl 1):i3-i14
26.
Holbein ME, Berglund JP. Understanding Food and Drug Administration regulatory requirements for an investigational device exemption for sponsor-investigators. J Investig Med 2012;60(7):987-94
27.
Available from: http://www1.astrazenecaus.com/pi/Nexium [Accessed 16 February 2014]
7
P. J. Parekh et al.
28.
Available from: http://www.hanmipharm. com/eng/release/board_read.asp? seq=564&board_id=7 [Accessed 16 February 2014]
29.
Pors nielsen S. The biological role of strontium. Bone 2004;35(3):583-8
30.
Available from: http://www.ema.europa. eu/docs/en_GB/document_library/ Press_release/2014/01/WC500159375 [Accessed 16 February 2014]
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
31.
32.
33.
34.
35.
8
36.
37.
Available from: http://apps.who.int/iris/ bitstream/10665/44280/1/ 9789241530774_eng?ua=1 [Accessed 16 February 2014] Hassan-alin M, Andersson T, Niazi M, et al. A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects. Eur J Clin Pharmacol 2005;60(11):779-84 Abel€ o A, Andersson TB, Antonsson M, et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 2000;28(8):966-72 Andersson T, R€ohss K, Bredberg E, et al. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 2001;15(10):1563-9 Lindberg P, Keeling D, Fryklund J, et al. Review article: esomeprazole–enhanced bio-availability, specificity for the proton
adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther 2006;24(2):377-85
pump and inhibition of acid secretion. Aliment Pharmacol Ther 2003;17(4):481-8
38.
39.
Wrighton SA, Vandenbranden M, Ring BJ. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996;24(5):461-73 Zanger UM, Turpeinen M, Klein K, et al. Functional pharmacogenetics/ genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 2008;392(6):1093-108 Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002;41(12):913-58 Sahara S, Sugimoto M, Uotani T, et al. Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole. Aliment Pharmacol Ther 2013;38(9):1129-37
40.
Available from: http://www.toxicology. org/ai/pub/tox/2013ToxSup [Accessed 16 February 2014]
41.
Moon B, Lee S, Han K, et al. Influence of clinical demographic factors in successful eradication of Helicobacter pylori [abstract]. Helicobacter 2011;16(Suppl 1):119:abstract P07.13
42.
Van soest EM, Siersema PD, Dieleman JP, et al. Persistence and
Expert Opin. Pharmacother. (2014) 15(9)
43.
Available from: http://www.goodrx.com/ dexilant [Accessed 16 February 2014]
44.
Available from: https://www.dexilant. com/Savings.aspx [Accessed 16 February 2014]
45.
Available from: http://www.goodrx.com/ omeprazole [Accessed 16 February 2014]
46.
Available from: http://www.goodrx.com/ esomeprazole-strontium [Accessed 16 February 2014]
47.
Available from: http://www.goodrx.com/ nexium [Accessed 16 February 2014]
48.
Available from: https://www.purplepill. com/taking-nexium/card.aspx?_ ziplist=disable [Accessed 16 February 2014]
Affiliation Parth J Parekh1 MD, Edward C Oldfield IV2 MD & David A Johnson†3 MD MACG FASGE FACP † Author for correspondence 1 Eastern Virginia Medical School, Department of Internal Medicine, Norfolk, VA, USA 2 Eastern Virginia Medical School, Norfolk, VA, USA 3 Eastern Virginia Medical School, Gastroenterology Division, Department of Internal Medicine, Norfolk, VA, USA E-mail: [email protected]
Review
1.
Introduction
2.
Dexlansoprazole MR
3.
Esomeprazole strontium
4.
Conclusion
5.
Expert opinion
Treatment of gastroesophageal reflux disease: two new oral formulations dexlansoprazole MR and esomezol (esomeprazole strontium) Parth J Parekh, Edward C Oldfield IV & David A Johnson† †
Eastern Virginia Medical School, Gastroenterology Division, Department of Internal Medicine, Norfolk, VA, USA
Introduction: The prevalence of gastroesophageal reflux disease continues to increase with the aging population and the obesity epidemic. Therapeutic failures can have significant detrimental effects in patients. Recently, dexlansoprazole MR and esomeprazole strontium were introduced to the class of proton pump inhibitors (PPIs). Areas covered: This article will review the pharmacodynamics and pharmacokinetics of dexlansoprazole MR and esomeprazole strontium. Using the keywords ‘dexlansoprazole MR’ and ‘esomeprazole strontium’ in the search engines of PubMed, Cochrane Reviews and Google, we were able to identify peer-reviewed publications, abstracts and presentations at national society educations meetings and present a balanced view of the available data. Expert opinion: Dexlansoprazole MR and esomeprazole strontium offer an innovative delivery mechanism compared to conventional PPIs. Further trials are necessary in order to establish superiority. Keywords: dexlansoprazole MR, esomeprazole strontium, gastroesophageal reflux disease, proton pump inhibitors Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Gastroesophageal reflux disease (GERD) currently affects 20 -- 40 million people in the USA, the prevalence of which continues to increase with the aging population and the obesity epidemic [1,2]. Proton pump inhibitors (PPIs) are widely recognized as being superior to other antisecretory therapies, and thus have become the cornerstone of pharmacological therapy for the treatment of GERD [3]. Despite their established benefits, there are several factors implicated in PPI treatment failure as outlined in Table 1, most notably visceral hypersensitivity, which may be attributed to the non-esophageal reflux disease (NERD) phenotype, compliance and suboptimal pH control [4]. Recent advances in the medical management of GERD attempt to target the latter two limitations of PPI therapy. Although little is understood about the NERD phenotype, the most recent data suggest that those with NERD display variability in their response to PPI therapy but ultimately do not carry the downstream complications of treatment failure as do those with GERD [5]. Treatment failure in patients with GERD can result in the emergence of erosive esophagitis and its complications such as strictures, bleeding and the development of Barrett’s esophagus with or without dysplasia [6]. Dexlansoprazole MR and esomeprazole strontium are the newest PPI options and these may be of benefit to certain patient populations. This article will review the most current literature 10.1517/14656566.2014.911841 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
P. J. Parekh et al.
Article highlights. .
.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
.
.
.
.
Dexlansoprazole MR offers a new innovative delivery mechanism where the initial drug release is in the proximal small intestine with subsequent release in various regions of the distal small intestine several hours later. Recent clinical trials have demonstrated dexlansoprazole MR to be as efficacious as other proton pump inhibitors (PPIs). The key advance in technology with the dual delay release formulation offers a twice-daily dosing effect in a one-time dose that may potentially enhance compliance or patient preference in the subset of patients who require twice-daily dosing. Esomeprazole strontium is an incrementally modified drug of esomeprazole magnesium using strontium salts rather than magnesium salts. Esomeprazole strontium is clinically identical to esomeprazole magnesium; however, at this time, there is insufficient clinical data comparing esomeprazole strontium with esomeprazole magnesium to draw a definite conclusion. Further clinical trials are necessary for both dexlansoprazole MR and esomeprazole strontium to prove superiority over the current available PPIs.
This box summarizes key points contained in the article.
Table 1. Cases of proton pump inhibitor therapy failure. Reason
Clinical implication
Compliance Helicobacter pylori
High Low -- no dose adjustment necessary Low -- no dose adjustment necessary; response rates among PPIs usually comparable Low Low Unclear High High -- may be as a result of NERD phenotype
Bioavailability
Nocturnal acid breakthrough Rapid metabolism/resistance NERD Delayed gastric emptying Visceral hypersensitivity
Data taken from [4]. NERD: Non-erosive reflux disease.
evaluating the pharmacodynamics and pharmacokinetics of dexlansoprazole MR and esomeprazole strontium. Additionally, a brief review of safety and efficacy from published clinical trials is provided. 2.
Dexlansoprazole MR
The most recent consensus guidelines addressed the discordance in the use of twice-daily PPI therapy typically used in clinical arena that is not typically addressed in clinical trial 2
data, despite the pharmacodynamics supporting twice-daily dosing [6-8]. Experts typically recommend the use of twicedaily PPI therapy to provide symptomatic relief in patients who have incomplete resolution of GERD-related symptoms to once-daily dosing. The advent of dexlansoprazole MR (Takeda Pharmaceuticals, Osaka, Japan) employs a novel approach by which its dual delayed release (DDR) formulation prolongs the plasma concentration ultimately extending the duration of acid suppression [8]. Pharmacokinetics and pharmacodynamics Dexlansoprazole MR is the R-enantiomer of the racemate lansoprazole, which selectively inhibits H+/K+ ATPase enzyme of gastric parietal cells resulting in suppression of acid secretion [9]. Following administration of lansoprazole, dexlansoprazole is the predominant circulating enantiomer accounting for approximately 80% of active metabolites of lansoprazole [10]. Dexlansoprazole MR utilizes DDR technology, which differs from conventional PPI delivery systems employing either immediate or delayed single-release formulations [11]. The DDR technology allows for an initial drug release in the proximal small intestine with subsequent release in various regions of the distal small intestine several hours later, resulting in a dual-peaked profile as compared to the single peak seen with conventional single-release PPIs. Higher doses of dexlansoprazole MR are required in order to maintain prolonged plasma concentrations and increased intragastric pH over a 24-h period. Metz et al. found the mean AUC and Cmax for dexlansoprazole MR (60, 90 and 120 mg) to be 3 -- 7 and 1.5 -- 3 times higher than compared to lansoprazole, respectively [10]. 2.1
Indications and usages Current manufacturer recommendations for dexlansoprazole in the adult population are for the treatment of healing all grades of erosive esophagitis (60 mg daily for 8 weeks), healing of erosive esophagitis (30 mg daily for up to 6 months), relief of reflux symptoms and the reflux associated with symptomatic non-erosive GERD (30 mg daily for 4 weeks) [11]. Dexlansoprazole can be taken with or without food, as there is no alteration of the bioavailability -- clearly there is a difference from all other PPIs [12]. Some patients, however, are more likely to have resolution of symptoms if taking therapy approximately 30 -- 60 min prior to a meal. 2.2
Safety and adverse effects In the clinical trials, the most commonly reported adverse effects of dexlansoprazole therapy were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%) and flatulence (1.6%) [6,13-16] As a whole, PPI therapy has been implicated with an increased risk of Clostridium difficile-associated diarrhea [17] and hypomagnesaemia [18] with prolonged treatment albeit rare. 2.3
Expert Opin. Pharmacother. (2014) 15(9)
Treatment of GERD
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
2.4
Clinical trials
A recent double-blind, randomized trial (performed at two different academic centers) evaluated the efficacy and safety of dexlansoprazole MR in healing erosive esophagitis [6]. Sharma et al. randomized 4092 patients to receive either dexlansoprazole MR (60 or 90 mg) or lansoprazole (30 mg) once daily, with primary endpoint assessing for healing using a closed testing procedure at week 8. They found that 92 -- 95% of patients were healed using dexlansoprazole MR versus 86 -- 92% of patients using lansoprazole; however, the differences were not statistically significant (p > 0.025). Crude rate analysis proved dexlansoprazole MR (90 mg) to be superior to lansoprazole in both studies, and the 60 mg formulation to be superior to lansoprazole in one study. An integrated analysis of 8-week healing in patients with moderate--severe erosive esophagitis yielded dexlansoprazole MR (90 mg) superior to lansoprazole, which led the authors to conclude dexlansoprazole MR effective in healing erosive esophagitis with benefits over lansoprazole, particularly in patients suffering from moderate to severe disease. Metz et al. sought to assess the efficacy and safety of dexlansoprazole MR in maintaining healed erosive esophagitis and symptomatic relief [19]. This double-blind trial randomized 445 patients with healed erosive esophagitis to receive dexlansoprazole MR (30 or 60 mg once daily) or placebo once daily for 6 months, with a primary endpoint of maintained endoscopic healing and secondary endpoints of continued symptom relief. They found maintenance rates in patients who received dexlansoprazole MR 30 mg, 60 mg and placebo to be 75, 83 and 27%, respectively, and that dexlansoprazole controlled heartburn (median of 91 -- 96% for 24-h heartburn-free days, 96 -- 99% for heartburn-free nights, which led to the conclusion that dexlansoprazole MR is efficacious in maintaining erosive esophagitis and providing symptomatic relief with a majority of patients being heartburn free for > 90% of days. Lastly, Fass et al. sought to evaluate the effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD [14]. They randomized 305 patients with moderate to very severe nocturnal heartburn and associated sleep disturbances to dexlansoprazole MR 30 mg or placebo once daily for 4 weeks. Patients who received dexlansoprazole MR were significantly less likely to experience nocturnal symptoms and associated sleep disturbances as compared to their placebo counterpart. The median percentage of nights without heartburn was 73.1% in the dexlansoprazole MR group compared to 35.7% in the placebo group (p < 0.001). In addition, dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of GERD-related sleep disturbances and nocturnal heartburn (69.7 vs 47.9% and 47.5 vs 19.6%, respectively; p < 0.001), which led the authors to conclude dexlansoprazole MR to be significantly more efficacious than placebo in reducing GERD-related sleep disturbances and symptomatic relief from nocturnal heartburn.
Bottom line: Currently, there is limited clinical data evaluating the efficacy of dexlansoprazole MR compared to conventional PPI therapy. The available data suggest that the higher doses of dexlansoprazole MR utilized in clinical trials are superior to traditional lansoprazole although there are no comparative trials to other PPIs. The key advance in technology with the dual delay release formulation offers a twice-daily dosing effect in a one-time dose that may potentially enhance compliance or patient preference in the subset of patients who require twice-daily dosing. Additionally, the lack of bioavailability effect when given with food may have a unique advantage for some patients where there are problems in compliance with the traditional instructions to take these medications 30 -- 60 min before breakfast. 3.
Esomeprazole strontium
In October 2010, Hanmi Pharmaceuticals (Seoul, South Korea) submitted a new drug application to the FDA for the approval of esomeprazole strontium, an incrementally modified drug of esomeprazole magnesium (Nexium) using strontium salts rather than magnesium (Mg) salts [20]. On August 6, 2013, the FDA granted marketing authorization for esomeprazole strontium [21]. The product will be released by Hanmi’s US marketing partner, Amneal Pharmaceutical (Bridegewater, NJ, USA) [22]. The FDA submission and drug approval does not provide specific clinical studies for esomeprazole strontium; rather, the extensive documentation of clinical studies for esomeprazole magnesium is cited in its place [23]. Esomeprazole is thermally unstable by itself and a stable crystalline form is needed to provide a pure and clinically useful dosage formulation. The crystalline formulation, esomeprazole magnesium (Nexium), was developed and ultimately commercially released in 2000. More recently, esomeprazole strontium was developed using strontium to provide a new crystalline salt for esomeprazole. Strontium is a trace metal in the human body that is a member of the same group of elements as Mg. In this respect they share many of the same chemical properties. Strontium has a mean bioavailability of about 20% with one study showing variations between 25% without a meal and 19% with a meal [24]. This is similar to the bioavailability of Mg with bioavailability around 24% under normal physiologic conditions [25]. The use of a strontium salt makes esomeprazole strontium a pharmaceutical alternative, which by definition from the FDA means ‘a drug product that contains the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester’ [26]. Esomeprazole strontium and esomeprazole magnesium are also said to be bioequivalent, which according to the FDA definition means the absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action when administered at the same molar
Expert Opin. Pharmacother. (2014) 15(9)
3
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
P. J. Parekh et al.
dose under similar conditions in an appropriately designed study. Bioequivalence was shown with 49.3 mg esomeprazole strontium achieving Cmax at approximately 1.7 h compared to 1.6 h for esomeprazole magnesium 40 mg. Additionally, the AUC that measures the mean exposure to esomeprazole was shown to be similar between the two formulations, which remained the case under both fasting conditions and also after 5 days of consecutive dosing [27]. The bioequivalence of esomeprazole strontium and esomeprazole magnesium has also reportedly been studied in a number of clinical trials; however, a search of available literature in the PubMed, Clinical Key and Science Direct databases as well as a search of clinical trials listed in ClinicalTrials.gov, the European Union Clinical Trials register and the South African National Clinical Trials Register fails to identify any studies on the topic [28]. Further evidence for the use of strontium in other pharmaceuticals is also based on its similarity to other elements in this same group as magnesium, in particular calcium (Ca), with which strontium shares a close resemblance. The similarity between strontium and Ca is close enough that it has been substituted for Ca in kinetic studies, in particular given its affinity for bone [29]. Elsewhere in the body, strontium and Ca compete for both intestinal absorption and renal tubular reabsorption; however, under normal physiologic conditions, the body is able to discriminate between the two elements. This similarity between these two elements has allowed for the development of strontium-containing compounds in the treatment of osteoporosis. Strontium ranelate has been shown to reduce the incidence of hip fractures and vertebral fractures in postmenopausal osteoporosis. The proposed mechanism relies on enhanced cell replication and bone formation via the activation of a Ca-sensing receptor thereby acting as an osteoblast agonist. The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee, however, has recently issued statement that strontium ranelate should no longer be used in the treatment of osteoporosis due to the increased risk for major adverse events [30]. These include 4 additional serious cardiac events and venous thromboembolism for every 1000 patient years and also an increased risk for serious skin reactions, disturbances in consciousness, seizures, liver inflammation and decreased number of red blood cells. The adverse effects of strontium, alone, do not reflect the same severity as those now identified for strontium ranelate; however, strontium’s close relationship with the activity of Ca may be the basis for some of the adverse effects of excess strontium. These adverse effects appear to be related to changes in the physiologic effects of Ca and vitamin D, more specifically the occurrence of rachitic lesions resulting from the impairment in intestinal absorption of Ca and renal production of 1, 25-dihydroxycholecalciferol [29]. Lastly, the risk of daily exposure to strontium appears minimal as animal models on the toxicity of strontium, with doses up to 40 mg/kg, showed only increased thyroid weight and increased levels of strontium in bone; however, no effects on bone were demonstrated [31]. 4
Pharmacokinetics and pharmacodynamics As there is currently only one study that includes a comparison between esomeprazole strontium to esomeprazole magnesium, much of the proposed difference in physiologic effect of esomeprazole strontium over other PPIs comes from the clinical trials of esomeprazole magnesium cited in the prescribing information [23]. Esomeprazole magnesium has been extensively studied, especially in comparison to its enantiomer, omeprazole. Some of the main differences between omeprazole and esomeprazole are related to differences in metabolism by the hepatic CYP enzymes, in particular CYP 2C19. Compared to omeprazole, esomeprazole is cleared more slowly than omeprazole, since it undergoes a less-extensive first-pass metabolism, and it also has minor CYP2C19 involvement, with 40% clearance for esomeprazole compared to 87% for omeprazole [32,33]. These two features translate into an enhanced bioavailability, increased specificity for the proton pump and increased inhibition of acid secretion due to a longer area under the plasma concentration--time curve [34,35]. Of note, esomeprazole does have some CYP 3A4 metabolism. In this respect, esomeprazole has the potential for increased drug--drug interactions, as CYP 3A4 is the major CYP enzyme responsible for 50% of drug metabolism [36]. Since the CYP enzymes extensively metabolize PPIs, in particular CYP 2C19, variations in the CYP 2C19 genotypes across populations can affect the metabolism and activity of PPIs. These differences have been shown with poor (PM) and intermediate metabolizers (IM) having both increased plasma levels of the active compound and acid inhibition as compared to the rapid metabolizers (RM) [37]. These polymorphisms, while most pronounced in East Asian populations, may still affect up to 30% of the white population [38]. The clinical significance of these polymorphisms on PPI function was recently addressed in a Japanese study that analyzed the CYP219 genotypes of 40 Helicobacter pylori negative volunteers and compared the median pH values between treatment with esomeprazole, omeprazole, lansoprazole and rabeprazole in PM, IM and RM CYP2C19 metabolizers [39]. Results of the study revealed that the median intragastric pH was higher than 5.0 in all PMs and IMs independent of the PPI used; however, in the RM group, the median intragastric pH for esomeprazole was significantly higher at 5.4 compared to the other PPIs, all < 5.0. While the authors of this study did note that the results could not be extrapolated to western countries due to wide variability in the CYP genotypes, the results of this study do suggest that esomeprazole may have increased effectiveness when compared to other PPIs on the basis of less-extensive CYP2C19 metabolism. 3.1
Indications and usages [23] The current indications for esomeprazole strontium in the adult population include the treatment of GERD, risk reduction of NSAID-associated gastric ulcers, H. pylori eradication 3.2
Expert Opin. Pharmacother. (2014) 15(9)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
Treatment of GERD
to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions including Zollinger-Ellison syndrome. Esomeprazole strontium is available in 24.65 and 49.3 mg tablets, equivalent to esomeprazole magnesium 20 and 40 mg, respectively. Esomeprazole strontium will be available in two different preparation/routes of administration, oral and nasogastric tube. The oral delayed-release capsules should be swallowed whole or opened and mixed with applesauce; the granules should not be chewed or crushed. For nasogastric preparation, the capsule can be opened and intact granules emptied into a catheter-tipped syringe for delivery through nasogastric tube. Gastroesophageal reflux disease Esomeprazole strontium is indicated at a dose of 24.65 or 49.3 mg (20 and 40 mg esomeprazole equivalents) once daily for 4 -- 8 weeks for the healing of erosive esophagitis with an additional consideration of 4 -- 8 weeks of treatment for those who do not heal. For the maintenance of healing of erosive esophagitis, esomeprazole strontium is indicated once daily at a dose of 24.65 mg (20 mg esomeprazole equivalent). Symptomatic treatment of GERD with esomeprazole strontium is indicated at a dose of 24.65 mg (20 mg esomeprazole equivalent) once daily for up to 6 months. Of note, the controlled studies for the use of esomeprazole strontium on GERD did not extend beyond 6 months. 3.2.1
Risk reduction of NSAID-associated gastric ulcer Esomeprazole strontium is indicated for risk reduction of NSAID-associated gastric ulcers at a dose of 24.65 or 49.3 mg (20 and 40 mg esomeprazole dose equivalents) once daily for up to 6 months. Those considered high risk for NSAID-associated ulcers are those over 60 years of age and/or with a documented history of gastric ulcers. 3.2.2
H. pylori eradication Esomeprazole strontium has been studied in combination with amoxicillin and clarithromycin as triple therapy for the eradication of H. pylori. The 10-day triple therapy consists of esomeprazole strontium administered once daily at a dose of 49.3 mg (40 mg esomeprazole equivalent) in combination with twice-daily 1000 mg amoxicillin and 500 mg clarithromycin. 3.2.3
Pathologic hypersecretory conditions Esomeprazole strontium is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome, at a dose of 49.3 mg (40 mg esomeprazole equivalent) twice daily. The dosages were noted to vary by the individual patient with doses up to 240 mg daily being administered [23]. In conclusion, the indications for esomeprazole strontium are the same as those of esomeprazole magnesium, including 3.2.4
treatment of GERD, risk reduction of NSAID-associated gastric ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, and pathological hypersecretory conditions, including Zollinger-Ellinson syndrome [27]. Safety and adverse events The FDA prescribing information for esomeprazole strontium cites the clinical studies of esomeprazole magnesium [23]. The most frequently occurring adverse events (occurring in > 1%) were headache, diarrhea, nausea, flatulence, abdominal pain, constipation and dry mouth. The same class effects of PPIs apply to esomeprazole strontium, which include an increased risk of C. difficile-associated diarrhea [17], and hypomagnesaemia [18]. Currently, there are no adequate well-controlled trials to assess the safety of esomeprazole strontium for use in the pregnant population. Rather, evidence for the safety of esomeprazole strontium in pregnant women comes from animal models comparing the effects of esomeprazole strontium versus esomeprazole magnesium. Comparison of the effects on embryo-fetal development from gestational day 6 through gestational day 20 at doses of 0, 14, 69 and 280 mg/kg/day (up to 57 times the maximum recommended human dose [MRHD]) showed no developmental toxicity at any dosage level of esomeprazole strontium or esomeprazole magnesium [40]. Next, using the same doses, the pre- and postnatal effects of esomeprazole strontium versus esomeprazole magnesium were compared from gestational day 6 through lactation day 21 [40]. At doses equal to or greater than 69 mg (16.8 times the MRHD), esomeprazole strontium and esomeprazole magnesium were equivalent for decreased survival, body weight and body weight gain and neurobehavioral or general developmental delays in the immediate post-weaning timeframe. Doses greater than 14 mg/kg/day (3.4 times the MRHD) were associated with decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity. If doses were increased to > 138 mg/kg/day (33.6 times the MRHD), physeal dysplasia in the femur was observed. Overall, there were no effects related directly to the strontium salt, rather the toxicity was attributable to the esomeprazole. Lastly, the researchers evaluated the comparative effects of esomeprazole strontium and esomeprazole magnesium on juvenile rats, postnatal days 7 -- 35 [40]. For doses of 70, 140 and 280 mg/kg/day, reduced survival, alterations in erythrocyte parameters, reduced mean body weights and food consumption, intestinal metaplasia of the glandular stomach and perivascular infiltrates of the lunges were noted. Similar to the prenatal and postnatal data, no adverse effects were directly attributable to the strontium salt, but attributable to the esomeprazole. Esomeprazole strontium has been labeled Pregnancy Category C as a result of these toxicology trials and the lack of any well-controlled studies in pregnant women [23]. 3.3
Expert Opin. Pharmacother. (2014) 15(9)
5
P. J. Parekh et al.
Clinical trials A search of currently published literature failed to identify any clinical studies comparing esomeprazole strontium and esomeprazole magnesium. There were, however, scientific abstracts available comparing esomeprazole strontium and esomeprazole magnesium. One Korean study from 2011 compared the effectiveness of various PPIs (esomeprazole magnesium and esomeprazole strontium, included) on the eradication of H. pylori [41]. Researchers enrolled patients to receive a 7-day treatment course with lansoprazole, rabeprazole, esomeprazole strontium or esomeprazole magnesium in addition to amoxicillin and clarithromycin. Urea breath test was performed 4 weeks later to assess therapy responsiveness. The overall eradication rate in the study was 70.9% (546/770) with esomeprazole magnesium achieving the highest response rate at 76% (225/297), while for esomeprazole strontium the eradication rate was 66.7% (96/144). Bottom line: Esomeprazole strontium is a new formulation of esomeprazole that uses a strontium salt to improve on the solubility of esomeprazole that is currently approved for the same indications as esomeprazole magnesium. Esomeprazole strontium should likely be clinically identical to esomeprazole magnesium (as implied by identical indications and product labeling); however, without data from head-to-head clinical comparisons it is impossible to draw a definite conclusion. There is nothing available, however, to suggest that this agent would have any superior clinical effects compared to the parent compound esomeprazole magnesium.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
3.4
4.
Conclusion
Dexlansoprazole MR represents a new PPI formulation that builds on isomeric purification by combining with a dual delay release formulation, which prolongs the plasma concentration and duration of acid suppression. The lack of food impairment for diminishing either the pharmacokinetic or pharmacodynamic effect is notable and may be discriminatory for optimizing compliance and acid inhibitory effect in selected patients. Clinical trials of dexlansoprazole MR at this time point to evidence that dexlansoprazole MR is similar in efficacy when compared to lansoprazole for the healing of erosive esophagitis [6], maintenance of erosive esophagitis [19] and the reduction of GERD-related nocturnal symptoms and associated sleep disturbances [14]. Its dual release formulation may potentially increase compliance rates in the subset of patients normally requiring twice-daily dosing; however, there is insufficient clinical data at this point to support this hypothesis. Esomeprazole strontium represents a new formulation of esomeprazole magnesium. At this time, there is insufficient clinical data comparing esomeprazole strontium with esomeprazole magnesium to draw a definite conclusion. Future clinical studies may serve to further elucidate any significant differences between the two formulations, including relative safety in human subjects and differences in efficacy for the treatment of indicated conditions. 6
5.
Expert opinion
This discussion of these two new pharmacologic agents for the treatment of GERD highlights some important issues facing effective healthcare delivery, namely adherence and cost. While many discussions are focused on the overuse of PPIs for patients with severe disease, adherence represents a significant barrier to therapeutic success. As discussed, there is a subset of patients considered as treatment failures, in particular those who did not respond to twice-daily PPI dosing and continue to experience disease sequelae. A recent review of 16,311 patients prescribed PPIs revealed that patients are less likely to adhere to treatment with twice-daily dosing [42]. Therefore, the ability to offer effective treatment with oncedaily dosing may prove to increase adherence rates among those requiring long-term therapy. Dexlansoprazole MR is one such agent whose innovative drug delivery system offers the pharmacokinetics of twice-daily dosing in a once-daily dose. Unfortunately, cost may preclude a majority of patients from benefitting from these new agents. Dexlansoprazole MR starts around $180 for a 30-day supply, although there is a pharmacy savings card available to cover up to $55 per month after the first $20 of co-pay [43,44]. By comparison, generic omeprazole is available for $10 for a 30-day supply [45]. This represents a significant cost difference when considering long-term therapy. This tradeoff represents an important consideration that providers must be aware of when discussing treatment options for patients. Esomeprazole strontium represents the first alternative formulation of esomeprazole approved for sale in the US market. A search of local prices on GoodRx.com revealed a starting price for a 30-day prescription of esomeprazole strontium 49.3 mg to be roughly $70 [46]. Using the same search parameters, a 30-day supply of esomeprazole magnesium 40 mg costs around $240, which can be combined with a savings card from AstraZeneca that offers to pay up to $50 after the customer pays the first $25 of the co-pay [47,48]. Given the emphasis on healthcare reform and cost savings, the significant cost difference between these formulations may prove to affect consumer choices. With Nexium’s patent expiring in May 2014, the market may see significant changes in the near future. As discussed, however, there is a lack of head-to-head clinical trials on esomeprazole strontium versus esomeprazole at this time and is an area requiring further clinical investigation.
Declaration of interest DA Johnson is on the Advisory Board for Centocor, MedScape, JWatch Gastroenterology and Given and is a Consultant for Pfizer, Medivo. He is on Speaker’s Bureau for Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Pharmacother. (2014) 15(9)
Treatment of GERD
Bibliography
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002;122:1500-11
2.
El-serag HB, Graham DY, Satia JA, et al. Obesity is an independent risk factor for GERD symptoms and erosive esophagitis. Am J Gastroenterol 2005;100(6):1243-50
3.
4.
5.
6.
..
7.
8.
9.
Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association medical position statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135(4):1383-91; 1391.e1-5 Fass R, Shapiro M, Dekel R, et al. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease–where next? Aliment Pharmacol Ther 2005;22(2):79-94 Hershcovici T, Fass R. Nonerosive Reflux Disease (NERD) - an update. J Neurogastroenterol Motil 2010;16(1):8-21 Sharma P, Shaheen NJ, Perez MC, et al. Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation–results from two randomized controlled studies. Aliment Pharmacol Ther 2009;29(7):731-41 Large randomized control trial comparing dexlansoprazole MR to traditional PPI therapy. Vakil N, Van zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101(8):1900-20
10.
11.
Vakily M, Zhang W, Wu J, et al. Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials. Curr Med Res Opin 2009;25(3):627-38
12.
Lee RD, Vakily M, Mulford D, et al. Clinical trial: the effect and timing of food on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor– evidence for dosing flexibility. Aliment Pharmacol Ther 2009;29(8):824-33
13.
Available from: http://www.dexilanthcp. com/dosing [Accessed 21 December 2013]
14.
Fass R, Johnson DA, Orr WC, et al. The effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD. Am J Gastroenterol 2011;106(3):421-31 Demonstrated efficacy of dexlansoprazole MR on GERD-related sleep disturbances.
..
15.
16.
Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-28 Gremse DA. Lansoprazole: pharmacokinetics, pharmacodynamics and clinical uses. Expert Opin Pharmacother 2001;2(10):1663-70
Metz DC, Vakily M, Dixit T, et al. Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy. Aliment Pharmacol Ther 2009;29(9):928-37
..
17.
Peura DA, Metz DC, Dabholkar AH, et al. Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience. Aliment Pharmacol Ther 2009;30(10):1010-21 Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther 2009;29(7):742-54 Demonstrated the safety and efficacy of dexlansoprazole MR. Tleyjeh IM, Bin abdulhak AA, Riaz M, et al. Association between proton pump inhibitor therapy and clostridium difficile Expert Opin. Pharmacother. (2014) 15(9)
infection: a contemporary systematic review and meta-analysis. PLoS One 2012;7(12):e50836 18.
Johnson DA, Oldfield EC. Reported side effects and complications of long-term proton pump inhibitor use: dissecting the evidence. Clin Gastroenterol Hepatol 2013;11(5):458-64
19.
Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther 2009;29(7):742-54
20.
Available from: http://www.hanmipharm. com/eng/release/board_read.asp? seq=549&board_id=7 [Accessed 16 February 2014]
21.
Available from: http://www.hanmipharm. com/eng/release/board_read.asp? seq=652&board_id=7 [Accessed 16 February 2014]
22.
Available from: http://www.amneal.com/ headlines/archive/ESGPR002_Eso_Generic_Release_FINAL [Accessed 16 February 2014]
23.
Available from: http://dailymed.nlm.nih. gov/dailymed/lookup.cfm? setid=61a5a84e-0194-4f11-91f883d7ac404932 [Accessed 16 February 2014] Provided manufacturer recommendations as well as pharmacokinetics and pharmacodynamics of esomeprazole strontium.
.
24.
Sips AJ, Van der vijgh WJ, Barto R, et al. Intestinal absorption of strontium chloride in healthy volunteers: pharmacokinetics and reproducibility. Br J Clin Pharmacol 1996;41(6):543-9
25.
Jahnen-Dechent W, Ketteler M. Magnesium basics. Clin Kidney J 2012;5(Suppl 1):i3-i14
26.
Holbein ME, Berglund JP. Understanding Food and Drug Administration regulatory requirements for an investigational device exemption for sponsor-investigators. J Investig Med 2012;60(7):987-94
27.
Available from: http://www1.astrazenecaus.com/pi/Nexium [Accessed 16 February 2014]
7
P. J. Parekh et al.
28.
Available from: http://www.hanmipharm. com/eng/release/board_read.asp? seq=564&board_id=7 [Accessed 16 February 2014]
29.
Pors nielsen S. The biological role of strontium. Bone 2004;35(3):583-8
30.
Available from: http://www.ema.europa. eu/docs/en_GB/document_library/ Press_release/2014/01/WC500159375 [Accessed 16 February 2014]
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/06/14 For personal use only.
31.
32.
33.
34.
35.
8
36.
37.
Available from: http://apps.who.int/iris/ bitstream/10665/44280/1/ 9789241530774_eng?ua=1 [Accessed 16 February 2014] Hassan-alin M, Andersson T, Niazi M, et al. A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects. Eur J Clin Pharmacol 2005;60(11):779-84 Abel€ o A, Andersson TB, Antonsson M, et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 2000;28(8):966-72 Andersson T, R€ohss K, Bredberg E, et al. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 2001;15(10):1563-9 Lindberg P, Keeling D, Fryklund J, et al. Review article: esomeprazole–enhanced bio-availability, specificity for the proton
adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ther 2006;24(2):377-85
pump and inhibition of acid secretion. Aliment Pharmacol Ther 2003;17(4):481-8
38.
39.
Wrighton SA, Vandenbranden M, Ring BJ. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996;24(5):461-73 Zanger UM, Turpeinen M, Klein K, et al. Functional pharmacogenetics/ genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 2008;392(6):1093-108 Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002;41(12):913-58 Sahara S, Sugimoto M, Uotani T, et al. Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole. Aliment Pharmacol Ther 2013;38(9):1129-37
40.
Available from: http://www.toxicology. org/ai/pub/tox/2013ToxSup [Accessed 16 February 2014]
41.
Moon B, Lee S, Han K, et al. Influence of clinical demographic factors in successful eradication of Helicobacter pylori [abstract]. Helicobacter 2011;16(Suppl 1):119:abstract P07.13
42.
Van soest EM, Siersema PD, Dieleman JP, et al. Persistence and
Expert Opin. Pharmacother. (2014) 15(9)
43.
Available from: http://www.goodrx.com/ dexilant [Accessed 16 February 2014]
44.
Available from: https://www.dexilant. com/Savings.aspx [Accessed 16 February 2014]
45.
Available from: http://www.goodrx.com/ omeprazole [Accessed 16 February 2014]
46.
Available from: http://www.goodrx.com/ esomeprazole-strontium [Accessed 16 February 2014]
47.
Available from: http://www.goodrx.com/ nexium [Accessed 16 February 2014]
48.
Available from: https://www.purplepill. com/taking-nexium/card.aspx?_ ziplist=disable [Accessed 16 February 2014]
Affiliation Parth J Parekh1 MD, Edward C Oldfield IV2 MD & David A Johnson†3 MD MACG FASGE FACP † Author for correspondence 1 Eastern Virginia Medical School, Department of Internal Medicine, Norfolk, VA, USA 2 Eastern Virginia Medical School, Norfolk, VA, USA 3 Eastern Virginia Medical School, Gastroenterology Division, Department of Internal Medicine, Norfolk, VA, USA E-mail: [email protected]
