ABSTRACT
Title
Challenges in Widespread Use of Gastroprotection: is an NSAID/PPI Combination the Answer?
Authors
C. Scarpignato
Laboratory of Clinical Pharmacology, Division of Gastroenterology, Department of Clinical Sciences, University of Parma, Italy
Laboratory of Clinical Pharmacology, Division of Gastroenterology, Department of Clinical Sciences, University of Parma, Italy
Abstract
Amongst the different strategies to reduce the risk of gastro-duodenal mucosal injury, which occurs with NSAID treatment, co-therapy with proton pump inhibitor (PPI) is the most widely used. NSAID-injury is indeed a pH-dependent phenomenon: the lower intragastric acidity, the higher the probability of not getting mucosal damage. Unfortunately, however, gastroprotection is often underused and adherence to the treatment is generally poor. Indeed, eleven observational studies in 911.000 NSAID users showed that 76% of the patients with at least one GI risk factor received no prescription for gastroprotective agents with an NSAID. In addition, prescription of prophylactic gastroprotection adds to the pill burden in these patients and may complicate their daily regimens. Therefore, in clinical practice few patients who need gastroprotection get it, and those who get it may not take it.
Based on the PK and PD of PPIs, the use of a twice daily regimen may be worthwhile. All currently available PPIs have a short half-life and the antisecretory effect lasts about 4 to 5 h, during which any active H+,K+-ATPase inserted into the secretory canalicular membrane is blocked. After that time, however, any pump, which was at rest in the cytosol of the parietal cell or newly synthesized, has the ability to secrete acid. Thus, a PPI given once daily, in the morning before breakfast, has no meaningful effect on acid secretion during the subsequent evening or night. Indeed, healthy volunteers taking esomeprazole 40 mg om show a pH <2 for 40% of the time between midnight and 07:00 AM. Most preventive strategies with PPIs as co-therapy to date have given the PPI once daily, despite the NSAIDs being given twice daily or even at bedtime. Furthermore, naproxen (one of the most frequently prescribed NSAIDs) has a plasma half life of 12 to 15 h, is given twice daily and also displays a marked entero-hepatic circulation, which further exposes the GI mucosa to the noxious agent. It would therefore be more logical to give the PPI bid, before breakfast and dinner.
To overcome the above-mentioned limitations of gastroprotection, a single-tablet, fixed-dose combination of naproxen and esomeprazole magnesium has been developed in order to provide patients with a GI safer anti-inflammatory therapy and improve compliance and (as a consequence) clinical outcomes. It consists of an enteric-coated (EC) naproxen core surrounded by an immediate-release (IR) esomeprazole mantle, designed to deliver sequentially the gasoprotective agent followed by the NSAID. Compared to the standard, EC esomeprazole, which behaves as a delayed-release (DR) formulatiom, the IR one dysplays a quicker onset of antiscretory action and a better control of intragastric acidity during nighttime. This fixed combination, referred to as PN400 or Vimovo®, given bid, has recently been approved by FDA and EMA. Two pivotal studies showed that in at risk patients, compared to EC naproxen alone, PN400 significantly reduced the incidence of gastric and duodenal ulcers, regardless of low-dose aspirin use. Patients taking PN400 had significantly better upper gastrointestinal tolerability (with less dyspepsia and heartburn) compared with those treated with EC naproxen. Therefore - compared to traditional NSAIDs - this combination appears to be a GI safer alternative.
C. Scarpignato, R.H. Hunt. (2010) Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am 39: 433-464.
R.A. Moore et al. (2006) Nonsteroidal anti-inflammatory drugs (NSAIDs), cyxlooxygenase-2 selective inhibitors (coxibs) and gastrointestinal harm: review of clinical trials and clinical practice. BMC Musculoskelet Disord 7: 79.
S. Dhillon (2011) Naproxen/Esomeprazole fixed-dose combination: for the treatment of arthritic symptoms and to reduce the risk of gastric ulcers. Drugs Aging 28: 237-248.
Based on the PK and PD of PPIs, the use of a twice daily regimen may be worthwhile. All currently available PPIs have a short half-life and the antisecretory effect lasts about 4 to 5 h, during which any active H+,K+-ATPase inserted into the secretory canalicular membrane is blocked. After that time, however, any pump, which was at rest in the cytosol of the parietal cell or newly synthesized, has the ability to secrete acid. Thus, a PPI given once daily, in the morning before breakfast, has no meaningful effect on acid secretion during the subsequent evening or night. Indeed, healthy volunteers taking esomeprazole 40 mg om show a pH <2 for 40% of the time between midnight and 07:00 AM. Most preventive strategies with PPIs as co-therapy to date have given the PPI once daily, despite the NSAIDs being given twice daily or even at bedtime. Furthermore, naproxen (one of the most frequently prescribed NSAIDs) has a plasma half life of 12 to 15 h, is given twice daily and also displays a marked entero-hepatic circulation, which further exposes the GI mucosa to the noxious agent. It would therefore be more logical to give the PPI bid, before breakfast and dinner.
To overcome the above-mentioned limitations of gastroprotection, a single-tablet, fixed-dose combination of naproxen and esomeprazole magnesium has been developed in order to provide patients with a GI safer anti-inflammatory therapy and improve compliance and (as a consequence) clinical outcomes. It consists of an enteric-coated (EC) naproxen core surrounded by an immediate-release (IR) esomeprazole mantle, designed to deliver sequentially the gasoprotective agent followed by the NSAID. Compared to the standard, EC esomeprazole, which behaves as a delayed-release (DR) formulatiom, the IR one dysplays a quicker onset of antiscretory action and a better control of intragastric acidity during nighttime. This fixed combination, referred to as PN400 or Vimovo®, given bid, has recently been approved by FDA and EMA. Two pivotal studies showed that in at risk patients, compared to EC naproxen alone, PN400 significantly reduced the incidence of gastric and duodenal ulcers, regardless of low-dose aspirin use. Patients taking PN400 had significantly better upper gastrointestinal tolerability (with less dyspepsia and heartburn) compared with those treated with EC naproxen. Therefore - compared to traditional NSAIDs - this combination appears to be a GI safer alternative.
C. Scarpignato, R.H. Hunt. (2010) Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am 39: 433-464.
R.A. Moore et al. (2006) Nonsteroidal anti-inflammatory drugs (NSAIDs), cyxlooxygenase-2 selective inhibitors (coxibs) and gastrointestinal harm: review of clinical trials and clinical practice. BMC Musculoskelet Disord 7: 79.
S. Dhillon (2011) Naproxen/Esomeprazole fixed-dose combination: for the treatment of arthritic symptoms and to reduce the risk of gastric ulcers. Drugs Aging 28: 237-248.