Proton Pump Inhibitors Formulations Research Articles

Use of physiologically-based pharmacokinetic modeling to understand the effect of omeprazole administration on the pharmacokinetics of oral extended-release nifedipine.

Proton pump inhibitors (PPIs) can affect the release of drugs from their dosage forms invivo by elevating the gastric pH. Our recent clinical study has demonstrated that drug-drug interactions (DDIs) exist between a PPI, omeprazole, and nifedipine extended-release formulations, where systemic exposure of nifedipine was increased in subjects after multiple-dose pretreatment of omeprazole. However, the mechanism of the observed DDIs between omeprazole and nifedipine has not been well-understood, as the DDI may also be mediated through CYP3A4 enzyme inhibition in addition to the elevated gastric pH caused by omeprazole. This study used physiologically-based pharmacokinetic (PBPK) modeling and simulations to investigate the underlying mechanism of these complex DDIs. A formulation exhibiting differences in invitro dissolution across physiological pH range and another formulation where pH does not impact dissolution appreciably (e.g., an osmotic pump) were chosen to characterize the potential impact of pH. The PBPK models incorporated two-stage invitro release profiles via US Pharmacopeia 2 apparatus. PBPK simulations suggest that the elevated gastric pH following multiple-dose administration of omeprazole has a minimal effect on nifedipine pharmacokinetics (PKs), whereas CYP3A4-mediated DDI is likely the main driver to the observed change of nifedipine PKs in the presence of omeprazole. Compared to the osmotic formulation, the slightly increased exposure of nifedipine can be accounted for by the enhanced drug release in the pH-dependent formulation. The reported model-based approach may be useful in DDI risk assessments, product formulation designs, and bioequivalence evaluations.

Optimal Use of Proton Pump Inhibitors and Potassium-competitive Acid Blockers

A variety of proton pump inhibitors (PPIs) have been developed in Korea since the introduction of omeprazole (the first PPI) in 1989. PPIs have served as the basic therapeutic approach for the management of gastric acid-related diseases for 30 years and remain among the most widely used drugs. Recently, potassium-competitive acid blockers (PCABs) have been developed both in Korea and abroad, demonstrating superior or non-inferior effects compared to existing PPIs in treating gastroesophageal reflux disease or <i>Helicobacter pylori</i> eradication, among others. Indications vary based on the various types and dosages of PPIs and PCABs, and several factors, including patients’ underlying disease, safety profile, particularly with regard to drug-drug interactions, and types of formulations of PPIs and PCABs need to be considered prior to prescribing these medications. In this article, we discuss the criteria for reimbursement of various PPIs and PCABs in Korea, along with considerations for prescribing these drugs based on patients’ underlying diseases.

Use and inappropriate use of proton pump inhibitors in hospitalized patients

Background: The discovery of Helicobacter pylori infection in etiology of peptic ulcer disease and proton pump inhibitors (PPI) in management of upper gastrointestinal diseases had been the milestones in medical science. PPI are currently being both overused and misused. In countries like India, where over 500 branded formulations of PPI are available, probability of misuse and abuse increases exponentially. The aim of the study was to find out inappropriate use of PPI, among hospitalized patients.Methods: In order to find answer to the research question a cross sectional study was conducted in indoor patient of a tertiary care private hospital at Jaipur, Rajasthan. Patients of either sex, aged 18 years or above belonging to rural and urban communities were participating in study. The sample size was 500.Results: It was noted that Inappropriate PPI use was observed in most of the hospital admitted patients (78%). Most common diagnosis among inappropriate PPI use was dengue fever (due to increased number of dengue cases during study period), followed by cerebrovascular accidents and urinary tract infection. Most common indication for appropriate PPI use was stress ulcer prophylaxis, again in dengue case (due to cardinal manifestation of thrombocytopenia).Conclusions: Almost all patients were once prescribed PPI after admission and discharged on PPI (99.2%). Thus, we recommend evidence-based prescription of PPI, to reduce side effects and excess cost.

Potent Potassium-competitive Acid Blockers: A New Era for the Treatment of Acid-related Diseases.

Conventional proton pump inhibitors (PPIs) are used as a first-line therapy to treat acid-related diseases worldwide. However, they have a number of limitations including slow onset of action, influence by cytochrome P450 polymorphisms, unsatisfactory effects at night, and instability in acidic conditions. Alternative formulations of conventional PPIs have been developed to overcome these problems; however, these drugs have only introduced small advantages for controlling acid secretion compared to conventional PPIs. Potassium-competitive acid blockers (P-CABs) were developed and have beneficial effects including rapid, long-lasting, and reversible inhibition of the gastric hydrogen potassium ATPase, the proton pump of the stomach. Vonoprazan was recently innovated as a novel, orally active P-CAB. It is currently indicated for the treatment of gastric and duodenal ulcers, reflux esophagitis, and prevention of low-dose aspirin- or nonsteroidal anti-inflammatory drug-related gastric and duodenal ulcer recurrence in Japan. Vonoprazan does not require enteric coating as it is acid-stable, and it can be taken without food because it is quickly absorbed. Vonoprazan accumulates in parietal cells under both acidic and neutral conditions. It does not require an acidic environment for activation, has long-term stability at the site of action, and has satisfactory safety and tolerability. Thus, vonoprazan may address the unmet medical need for the treatment of acid-related diseases.

Interchangeable Use of Proton Pump Inhibitors Based on Relative Potency

Although proton pump inhibitors (PPIs) are widely used, their relative potency and ideal dosing regimens remain unclear. We analyzed data from randomized clinical trials that performed pH testing in patients receiving solid-dose PPI formulations (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) for a minimum of 5 days. We used omeprazole equivalency and the surrogate biomarker, percentage time pH > 4 over a 24-hour period (pH4time), to compare PPI effectiveness for different PPIs given once, twice, or 3 times daily. We found that increasing strength of once-daily PPIs (9-64 mg omeprazole equivalents) increased pH4time linearly from approximately 10.0 to 15.6 hours; higher doses produced no further increase in pH4time. Increasing the frequency to twice-daily PPI increased pH4time linearly, from approximately 15.8 to 21.0 hours. Three-times daily PPIs performed similarly to twice-daily PPIs. The costs of PPIs varied greatly, but the cost variation was not directly related to potency. We conclude that PPIs can be used interchangeably based on potency. Using twice-daily PPIs is more effective in increasing efficacy increasing once-daily PPI dosage. Omeprazole and lansoprazole (30 mg) and 20 mg of esomeprazole rabeprazole are functionally equivalent.

In vitro Approaches to Support Bioequivalence and Substitutability of Generic Proton Pump Inhibitors via Nasogastric Tube Administration

Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product. As part of the assessment of bioequivalence, the Office of Generic Drugs (OGD) has developed a suite of in vitro testing to compare the delivery of the generic and reference products via nasogastric tubes. These in vitro tests assess essential attributes associated with the likelihood of clogging and maintenance of the enteric coating. These in vitro tests include studies evaluating sedimentation, granule size distribution, drug recovery, and acid resistance. One of the challenges is that while the administration of PPIs through nasogastric tubes is common in clinical practice, this issue is not uniformly addressed in the FDA approved label of the reference drug products. This paper discusses the design and rationale for in vitro testing of PPI formulations with respect to bioequivalence via nasogastric tube administration and in addition, it summarizes commonly occurring deficiencies in the in vitro nasogastric tube testing of 14 recent Abbreviated New Drug Applications (ANDA) submitted for five generic PPI drug products.

Brand name and generic proton pump inhibitor prescriptions in the United States: insights from the national ambulatory medical care survey (2006-2010).

Introduction. Proton pump inhibitors (PPI) are one of the most commonly prescribed medication classes with similar efficacy between brand name and generic PPI formulations. Aims. We determined demographic, clinical, and practice characteristics associated with brand name PPI prescriptions at ambulatory care visits in the United States. Methods. Observational cross sectional analysis using the National Ambulatory Medical Care Survey (NAMCS) of all adult (≥18 yrs of age) ambulatory care visits from 2006 to 2010. PPI prescriptions were identified by using the drug entry code as brand name only or generic available formulations. Descriptive statistics were reported in terms of unweighted patient visits and proportions of encounters with brand name PPI prescriptions. Global chi-square tests were used to compare visits with brand name PPI prescriptions versus generic PPI prescriptions for each measure. Poisson regression was used to determine the incidence rate ratio (IRR) for generic versus brand PPI prescribing. Results. A PPI was prescribed at 269.7 million adult ambulatory visits, based on 9,677 unweighted visits, of which 53% were brand name only prescriptions. In 2006, 76.0% of all PPI prescriptions had a brand name only formulation compared to 31.6% of PPI prescriptions in 2010. Visits by patients aged 25–44 years had the greatest proportion of brand name PPI formulations (57.9%). Academic medical centers and physician-owned practices had the greatest proportion of visits with brand name PPI prescriptions (58.9% and 55.6% of visits with a PPI prescription, resp.). There were no significant differences in terms of median income, patient insurance type, or metropolitan status when comparing the proportion of visits with brand name versus generic PPI prescriptions. Poisson regression results showed that practice ownership type was most strongly associated with the likelihood of receiving a brand name PPI over the entire study period. Compared to HMO visits, patient visits at academic medical centers (IRR 4.2, 95% CI 2.2–8.0), physician-owned practices (IRR 3.9, 95% CI 2.1–7.1), and community health centers (IRR 3.6, 95% CI 1.9–6.6) were all more likely to have brand name PPIs. Conclusion. PPI prescriptions with brand name only formulations are most strongly associated with physician practice type.

Phase I, Multicenter, Randomized, Open-Label Study Evaluating the Pharmacokinetics and Safety Profile of Repeated Once-Daily Doses of Intravenous Esomeprazole in Children 0 to 17 Years of Age

BackgroundSeveral oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children. ObjectiveThe aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children. MethodsIn this multicenter, open-label study, hospitalized patients (0–17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0–1 month of age), 1.0 mg/kg (1–11 months of age), 10 mg (1–5 years of age), 10 or 20 mg (6–11 years of age), or 20 or 40 mg (12–17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed. ResultsFifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUCτ ranged from 6.9 μmol · h/L (10 mg, 6–11 years) to 17.6 μmol · h/L (40 mg, 12–17 years). The mean Css,max ranged from 3.7 μmol/L (0.5 mg/kg, 0–1 month) to 10.5 μmol/L (40 mg, 12–17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs. ConclusionsIntravenous esomeprazole at doses resulting in targeted AUCτ and Css,max similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019.

Review article: dual delayed release formulation of dexlansoprazole MR, a novel approach to overcome the limitations of conventional single release proton pump inhibitor therapy

Proton pump inhibitors (PPIs) provide the most effective pharmacotherapy for treating acid-related disorders. However, PPIs do not completely control acid over 24 h with once-daily dosing. To discuss limitations inherent in the pharmacokinetics (PK) and pharmacodynamics of conventional PPI formulations, which provide a single drug release. Also, to consider approaches to extending the duration of acid suppression focusing on dexlansoprazole MR, a PPI with a novel Dual Delayed Release (DDR) formulation. We reviewed the available literature regarding marketed and investigational PPIs. Non-standard dosing of currently marketed PPIs has produced incremental advances in acid control. Multiple approaches are being evaluated to enhance acid suppression with PPIs. Dexlansoprazole MR is a DDR formulation of dexlansoprazole, an enantiomer of lansoprazole, with two distinct drug release periods to prolong the plasma dexlansoprazole concentration-time profile and extend duration of acid suppression. Clinical studies show that dexlansoprazole MR produces a dual-peak PK profile that maintains therapeutic plasma drug concentrations longer than lansoprazole, with a single-peak PK profile, and increases the percentage of time that intragastric pH >4. Novel drug delivery platforms, including the dexlansoprazole MR DDR formulation, may improve acid suppression and offer benefits over conventional single release PPI formulations.

Can Acid Control Be Improved with a Modified-Release Formulation of a Proton Pump Inhibitor?

Purpose: Modified-release (MR) formulations of proton pump inhibitors (PPIs) are being investigated in attempts to improve upon the well-documented clinical efficacy of conventional formulations of PPIs by further increasing acid control. This dose-finding study assessed the pharmacodynamics of a once-daily MR formulation of esomeprazole (ESO), compared with conventional capsule formulations given twice daily (bid). Methods:Heliobacter pylori negative healthy adults were enrolled into this single-center, open, 5-way crossover study (AstraZeneca study code: D961CC00006). Subjects were randomized to standardized sequences of five 5-day ESO treatment periods (40 mg MR, 60 mg MR, 80 mg MR [given in the morning], 20 mg bid and 40 mg bid) separated by washout periods of ≥13 days. 24-h intragastric pH monitoring was performed under standardized conditions on day 5 of each treatment period. Statistical analysis comprised a mixed model ANOVA with fixed factors for period, sequence and treatment and a random factor for subject within sequence. Results: The per-protocol analysis of acid control included 39 subjects (20 males; mean age, 34 y). The results are presented in the table below. Esomeprazole was well tolerated and the safety evaluation did not raise any safety concerns. Conclusion: These results indicate that, among MR doses tested, 60 mg MR appears to be optimal for daytime, nighttime, and 24-h acid control. With the same daily dose of ESO, MR technology provided less 24-h and nighttime pH control than bid dosing.Table: Mean percentage time with intragastric pH > 4

Ninety‐six‐hour wireless oesophageal pH monitoring following proton pump inhibitor administration in NERD patients

Comparative studies of proton pump inhibitors (PPIs) have revealed that acid reflux is influenced by PPI treatment, formulations and dosing regimens. Wireless pH capsules have circumvented some of the limitations of conventional catheter-based pH testing with the additional advantage of 96-h recording periods. To clarify the effectiveness of intra-oesophageal acid suppression by omeprazole, pantoprazole and lansoprazole in non-erosive reflux disease patients through a 4-day monitoring of oesophageal pH and related symptoms. Twenty-four patients with typical symptoms of gastro-oesophageal reflux disease were enrolled and administered upper endoscopy and placement of a wireless pH capsule. Patients randomly received omeprazole, pantoprazole or lansoprazole for 3 days after the first 24 h. Symptom-reflux associations were expressed using the symptom index (SI). All patients completed the study. Significant decrease in acid exposure occurred on day 2 and in each successive day in all groups. Pantoprazole and omeprazole are more effective than lansoprazole at inducing a normalization of intra-oesophageal acid exposure at days 2 and 3. Significant reduction in SI at day 2 was observed. Four-day ambulatory oesophageal pH monitoring is feasible and safe. Omeprazole, pantoprazole and lansoprazole have an equivalent potency for normalizing intra-oesophageal acid exposure after 3 days of treatment in non-erosive reflux disease patients.

Intravenous esomeprazole 40 mg vs. intravenous lansoprazole 30 mg for controlling intragastric acidity in healthy adults

Intravenous (IV) formulations of proton pump inhibitors are effective for patients in whom oral therapy is not appropriate. To compare IV esomeprazole and IV lansoprazole for the control of intragastric pH. In this open-label crossover study, healthy, Helicobacter pylori-negative adults were randomized to one of two treatment sequences, each consisting of two 5-day dosing periods of IV esomeprazole 40 mg or IV lansoprazole 30 mg. Twenty-four-hour intragastric pH monitoring was conducted on days 1 and 5 of each dosing period. On days 1 and 5, intragastric pH was >4.0 significantly longer with esomeprazole than lansoprazole (least-squares means: day 1, 40.0% vs. 33.6%; day 5, 61.9% vs. 45.4%; both P < 0.0001). During the first 4 h of pH monitoring, intragastric pH was >4.0 significantly longer on days 1 and 5 with esomeprazole than lansoprazole (P < 0.0001). Kaplan-Meier estimates of median hours to stable pH >4.0 were 4.92 for esomeprazole and 5.75 for lansoprazole (P = 0.0014 for test on Gehan scores). In healthy adults, IV esomeprazole 40 mg controlled intragastric acidity faster and more effectively than IV lansoprazole 30 mg.

Omeprazole/Antacid-Powder Suspension ??? Santarus

Santarus Inc. is developing an immediate-release formulation of omeprazole in combination with an antacid (sodium bicarbonate) as a powder for suspension, known as Acitreltrade mark [SAN 05] and also as Rapinex powder for oral suspension. This omeprazole powder suspension will be used to treat gastrointestinal haemorrhage, gastro-oesophageal reflux disease, heartburn and peptic ulcers. Acitreltrade mark is based on technology licensed from the University of Missouri. Santarus have also licensed technology from Tulane and North Carolina Universities relating to potential treatments for gastrointestinal (GI) diseases. Santarus has licensed exclusive, worldwide rights to patent applications covering specific combination formulations of proton pump inhibitors (PPIs) and antacids for treating various upper GI diseases and disorders. Santarus plans to license the development, distribution and marketing rights of omeprazole powder for oral suspension 20 mg outside the US, to one or more well established pharmaceutical companies. The US FDA has requested that Santarus pursue a name other than Rapinex for the product. Santarus is currently discussing potential alternative names for the product with the FDA. Santarus announced positive results in August 2003 from a phase III trial comparing oral Acitrel (Rapinex 40 mg) with intravenous cimetidine in preventing upper GI bleeding in 359 critically ill adult patients. Santarus has also completed an open-label clinical trial in 243 patients, including 97 patients with gastric ulcers, evaluating the safety of this omeprazole 40 mg powder suspension for an 8-week period. In connection with the NDA for omeprazole powder suspension 40 mg, Santarus provided notice to the NDA holder for Prilosec delayed-release capsules and related patent owners that omeprazole powder suspension 40 mg does not infringe currently listed patents for Prilosec or that those patents are invalid.

Novel therapeutic strategies in acid-related disorders

Acid-related disorders of the upper gut encompass diseases of the oesophagus, stomach and duodenum, such as gastro-oesophageal reflux disease (GORD), gastric and duodenal (peptic) ulcers, Zollinger–Ellison syndrome and iatrogenic ulcers and gastrointestinal bleeding mostly induced by non-steroidal anti-inflammatory drugs (NSAIDs). Gastric acid and pepsin are largely involved in their pathophysiology, both factors acting with Helicobacter pylori (especially in peptic ulcers) or with either NSAIDs, stress or smoking. All these diseases can benefit from agents that neutralise gastric acid or inhibit its secretion. Neutralising acid with antacids or decreasing acid secretion with histamine H2-receptor antagonists (H2-RAs) was the standard of care before the introduction of proton pump inhibitors (PPIs), which have been one of the major advances in the field of gastrointestinal pharmacology. Their superior efficacy in acid-related disorders with respect to other acid reducing drugs is now widely recognised. PPIs are also used to control atypical GORD symptoms, such as laryngitis, asthma and cough associated with reflux. In spite of their clinical efficacy in a number of conditions, the emerging need for new therapeutic approaches, such as ‘on-demand’ treatment for GORD symptoms, requires some features (e.g., fast onset of action at day 1 with an acid suppressant effect throughout the day and night, to avoid the nocturnal acid breakthrough) that currently available PPIs only partially achieve. Moreover, a subset of patients with GORD still do not respond to the available therapeutic regimens. Novel agents (or novel formulations of available PPIs) have recently been patented to try to overcome these problems.

Review article: acid suppression in non-variceal acute upper gastrointestinal bleeding.

Despite a decreased incidence of ulcer disease and improvements in the management of acute upper gastrointestinal (GI) bleeding, mortality remains at about 6-7%. Although endoscopic haemostatic therapy has been demonstrated to be the mainstay of management, the search continues for less invasive medical modalities that might also improve patient outcome. In vitro data have indicated the important role of acid in impairing haemostasis and causing clot digestion. Therefore, theoretically, maintenance of a high intragastric pH (above 6.0) during management of upper GI bleeding is warranted. Until recently, available agents did not permit such a sustained elevation in gastric pH. Early studies with H2-receptor antagonists have not demonstrated significant improvements in important patient outcomes, such as rebleeding, surgery or mortality. With the availability of intravenous formulations of proton pump inhibitors, it is now possible to aim at maintaining gastric pH above 6.0 for 24 h per day. Recent clinical trial data would appear to support the use of proton pump inhibitors to decrease the rate of rebleeding and the need for surgery. This paper provides a review of non-variceal acute GI bleeding, with special reference to the role of proton pump inhibitors in this clinical setting.