Pancreatic Enzyme Products Research Articles

Study of the gastrointestinal bioavailability of a pancreatic extract product (Zenpep) in chronic pancreatitis patients with exocrine pancreatic insufficiency

IntroductionThe Food and Drug Administration in 2006 required that all pancreatic enzyme products demonstrate bioavailability of lipase, amylase, and protease in the proximal small intestine. MethodsIn this phase I open-label, randomized, crossover trial, 17 adult chronic pancreatitis (CP) patients with severe exocrine pancreatic insufficiency (EPI) underwent two separate gastroduodenal perfusion procedures (Dreiling tube suctioning and [14C]-PEG instillation by an attached Dobhoff tube in the duodenal bulb). Patients received Ensure Plus® alone and Ensure Plus with Zenpep (75,000 USP lipase units) in random order. The bioavailability of Zenpep was estimated by comparing the recovery of lipase, amylase, chymotrypsin activity in two treatment conditions. 14C-PEG was used to correct duodenal aspirates volume. The primary efficacy endpoint was lipase delivery in the duodenum after Zenpep administration under fed conditions. Secondary efficacy endpoints included chymotrypsin and amylase delivery, serum CCK levels, and measuring duodenal and gastric pH. ResultsZenpep administration with a test meal was associated with significant increase in duodenal aspiration of lipase (p = 0.046), chymotrypsin (p = 0.008), and amylase (p = 0.001), compared to the test meal alone, indicating release of enzymes to the duodenum. Lipase delivery was higher in the pH subpopulation (the efficacy population with acid hypersecretors excluded) (p = 0.01). Recovery of [14C]-PEG was 61%. Zenpep was generally well tolerated. All adverse events were mild and transient. ConclusionsIn CP patients with severe EPI, lipase, chymotrypsin and amylase were released rapidly into the duodenum after ingestion of Zenpep plus meal compared to meals alone. Results also reflected the known pH threshold for enzyme release from enteric coated products.

Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial

To evaluate the safety and efficacy of a novel microbial lipase (NM-BL) in a liquid formulation for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) in a phase IIa proof-of-concept study. We conducted a double-blind, randomized, placebo controlled crossover study in patients with cystic fibrosis and exocrine pancreatic insufficiency. Adolescent and adult patients with CF were randomized to receive NM-BL or placebo for 1week as replacement for their usual pancreatic enzyme formulation. They were subsequently crossed-over to the alternate study treatment. The coefficient of fat absorption was evaluated as the primary endpoint. Symptoms and adverse events were evaluated as secondary endpoints. A total of 35 patients were randomized into the study and 22 patients completed both treatment periods. During treatment with NM-BL, the coefficient of fat absorption was significantly greater (72.7%) compared with placebo (53.8%) with a difference between groups of 18.8% (P<.001). Subjective assessment of stool fat and stool consistency also improved under treatment with NM-BL. Adverse events were mostly gastrointestinal in nature and were more common in the group receiving NM-BL. Currently available pancreatic enzyme products are limited because of the lack of liquid formulations and being largely porcine based. The novel microbial lipase NM-BL was safe and effective in this short term trial. The trial provided clinical proof-of-concept for this novel microbial lipase as a treatment for EPI in CF. A larger phase 2 dose ranging trial is warranted. ClinicalTrials.gov: NCT01710644.

Comparison of two pancreatic enzyme products for exocrine insufficiency in patients with cystic fibrosis

BackgroundZenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF). MethodsZenpep and Kreon, both containing 25,000 lipase units, were compared in a randomised, double-blind, crossover, non-inferiority study for CF-associated EPI in patients aged ≥12years. Patients on a standardised diet and stabilised treatment were randomised to two treatment sequences: Zenpep/Kreon or Kreon/Zenpep. The primary efficacy endpoint was the coefficient of fat absorption over 72h (CFA-72h). Results96 patients (mean age 19.2years, 60.4% males) were randomised with 83 completers of both sequences comprising the efficacy population. Zenpep demonstrated non-inferiority and equivalence to Kreon in fat absorption (LS mean CFA-72h: Zenpep, 84.1% [SE 1.1] vs. Kreon, 85.3% [SE 1.1]; p=0.297). Safety and tolerability were similar. ConclusionsZenpep is comparable with Kreon in efficacy and safety for the treatment of adolescents and adults with CF-associated EPI.NCT01641393

The FDA and prescription pancreatic enzyme product cost.

The FDA and prescription pancreatic enzyme product cost.

Sacrificing Affordability in the Name of Proving Efficacy: The Case of Pancreatic Enzyme Replacement Therapy

Purpose: In 2004, under pressure from patient advocacy groups to ensure safety, effectiveness, and most importantly safe product interchange, the Food and Drug Administration (FDA) mandated that all pancreatic enzyme products (PEPs) be approved under a New Drug Application (NDA) by 2010. As a result of this requirement, the number of PEPs marketed in the United States for treatment of cystic fibrosis, pancreatic surgery, and chronic pancreatitis declined from approximately 30 different products in 2008 to currently only six. The aim of this study was to determine the effect of this intervention on the cost of and access to PEP prescriptions in the United States. Methods: Using the IMS Health Product Report 5.0 database, the total annual number of United States prescriptions and sales (U.S. dollars) from the years 2008-2012 for relevant PEPs were obtained. The study focused on three PEPs: Creon (AbbVie, North Chicago, IL), Pancrease/Pancreaze (Janssen Pharmaceuticals, Inc. Raritan, NJ), and Zenpep (Aptalis, Inc. Bridgewater, NJ), because all were approved prior to 2011, and thus, 1-year post-approval cost data were available. Prescription costs for each medication were calculated by dividing the annual total number of prescriptions by total sales. The primary outcome was the cost of each medication (with the exception of Zenpep, which was new in 2009) 1 year before and 1 year after FDA approval. Results: In the year prior to approval (2008), the mean prescription cost for Creon 10 and 20 formulations was $262 and $488, respectively. In 2010, the year after approval, prices were $350 for Creon 12 and $683 for Creon 24. Similarly, Pancreaze increased in price after its approval (2010) from $336 to $538. Zenpep, which debuted in 2009, was initially priced at $580. The total number of prescriptions for the most common PEP formulations (Creon, Pancrease/Pancreaze, Ultrase, Viokase/Viokace, Zenpep, Pancrelipase) was 631,291 in 2008, 876,226 in 2009 and 1,118,774 in 2010. No comparative efficacy or post-marketing surveillance studies have been published since the FDA requirement was enacted to ensure safe product interchange. Conclusion: The FDA NDA requirement for pancreatic enzyme products resulted in universal prescription price increases. No studies to ensure safe product interchange, the original goal of the NDA requirement, have been performed.

Su1322 Pancreatic Pseudoaneurysms With and Without Associated Pseudocysts: Non Surgical Management

Background: There are over 30,000 patients with cystic fibrosis and about 80,000 diagnosed each year with pancreatitis in the United States. Pancreatic enzyme products (PEPs) containing the active ingredient pancrelipase, a mixture of the digestive enzymes amylase, lipase, and protease are frequently prescribed to both groups. Case reports of fibrosing colonopathy with pancreatic enzyme supplements have been reported in children with cystic fibrosis and rarely in adults. We sought to identify adverse events affecting small and large intestines with the use of pancreatic enzyme supplements reported to a pharmacovigilance database using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: More than 3.1 million files between January 2003 and June 2012 were downloaded from the FAERS and analyzed using SPSS 20 (IBM Co. Armonk, NY). They were queried for Primary Suspect (PS) reports of adverse events with PEPs, using both trade and generic names. All approved indications were used, and the Medical Dictionary for Regulatory Activities (version 15.1 September 2012) was used to identify all primary and lower-level search terms. All reactions, after querying for indication and drug, were then hand searched for intestinal adverse events. Results: There were 114 PS cases (table 1) of small and large intestinal adverse events identified with PEPs. A total of 38 cases were associated with cystic fibrosis, 27 with pancreatitis, and 49 associated with unspecified pancreatic indications (pancreatic insufficiency, neoplasm of the pancreas, pancreatic operations, pancreatic disorders not otherwise specified). A majority of intestinal adverse events were found in females (52.2%). Average age of cases by indication of usage was 16±14 years for those with cystic fibrosis, 64±18 years for those with pancreatitis and 52±28 years for those with unspecified pancreatic indications. Diarrhea was the most common adverse reaction. We identified 17 cases of small or large intestinal obstruction. Three of the 17 obstruction cases had a concomitant medication which may have led to the obstruction (1 on meloxicam and 1 on loperamide leading to an intestinal obstruction, and 1 on oxycodone leading to a colonic obstruction). This results in an intestinal obstruction rate of 1.47 cases per year and a colonic obstruction rate of 0.32 cases a year, within the context of cases reported to the FDA. Conclusion: Diarrhea is most likely related to the underlying disease state. Serious complications such as small and large intestinal obstructions are rarely reported with PEPs in context of the large number of patients who are prescribed these drugs. More research is warranted to identify the at-risk patient population for serious intestinal adverse events associated with PEPs. Table 1: Small and large intestinal adverse reactions associated with pancrelipase tablets and delayed release capsules

Su1319 Intestinal Adverse Outcomes With Pancreatic Enzymes: An Analysis of the Food and Drug Administration Adverse Event Reporting System

Background: There are over 30,000 patients with cystic fibrosis and about 80,000 diagnosed each year with pancreatitis in the United States. Pancreatic enzyme products (PEPs) containing the active ingredient pancrelipase, a mixture of the digestive enzymes amylase, lipase, and protease are frequently prescribed to both groups. Case reports of fibrosing colonopathy with pancreatic enzyme supplements have been reported in children with cystic fibrosis and rarely in adults. We sought to identify adverse events affecting small and large intestines with the use of pancreatic enzyme supplements reported to a pharmacovigilance database using the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: More than 3.1 million files between January 2003 and June 2012 were downloaded from the FAERS and analyzed using SPSS 20 (IBM Co. Armonk, NY). They were queried for Primary Suspect (PS) reports of adverse events with PEPs, using both trade and generic names. All approved indications were used, and the Medical Dictionary for Regulatory Activities (version 15.1 September 2012) was used to identify all primary and lower-level search terms. All reactions, after querying for indication and drug, were then hand searched for intestinal adverse events. Results: There were 114 PS cases (table 1) of small and large intestinal adverse events identified with PEPs. A total of 38 cases were associated with cystic fibrosis, 27 with pancreatitis, and 49 associated with unspecified pancreatic indications (pancreatic insufficiency, neoplasm of the pancreas, pancreatic operations, pancreatic disorders not otherwise specified). A majority of intestinal adverse events were found in females (52.2%). Average age of cases by indication of usage was 16±14 years for those with cystic fibrosis, 64±18 years for those with pancreatitis and 52±28 years for those with unspecified pancreatic indications. Diarrhea was the most common adverse reaction. We identified 17 cases of small or large intestinal obstruction. Three of the 17 obstruction cases had a concomitant medication which may have led to the obstruction (1 on meloxicam and 1 on loperamide leading to an intestinal obstruction, and 1 on oxycodone leading to a colonic obstruction). This results in an intestinal obstruction rate of 1.47 cases per year and a colonic obstruction rate of 0.32 cases a year, within the context of cases reported to the FDA. Conclusion: Diarrhea is most likely related to the underlying disease state. Serious complications such as small and large intestinal obstructions are rarely reported with PEPs in context of the large number of patients who are prescribed these drugs. More research is warranted to identify the at-risk patient population for serious intestinal adverse events associated with PEPs. Table 1: Small and large intestinal adverse reactions associated with pancrelipase tablets and delayed release capsules

Impaired Small-Bowel Barrier Integrity in the Presence of Lumenal Pancreatic Digestive Enzymes Leads to Circulatory Shock

In bowel ischemia, impaired mucosal integrity may allow intestinal pancreatic enzyme products to become systemic and precipitate irreversible shock and death. This can be attenuated by pancreatic enzyme inhibition in the small-bowel lumen. It is unresolved, however, whether ischemically mediated mucosal disruption is the key event allowing pancreatic enzyme products systemic access and whether intestinal digestive enzyme activity in concert with increased mucosal permeability leads to shock in the absence of ischemia. To test this possibility, the small intestinal lumen of nonischemic rats was perfused for 2 h with either digestive enzymes, a mucin disruption strategy (i.e., mucolytics) designed to increase mucosal permeability, or both, and animals were observed for shock. Digestive enzymes perfused included trypsin, chymotrypsin, elastase, amylase, and lipase. Control (n = 6) and experimental animals perfused with pancreatic enzymes only (n = 6) or single enzymes (n = 3 for each of the five enzyme groups) maintained stable hemodynamics. After mucin disruption using a combination of enteral N-acetylcysteine, atropine, and increased flow rates, rats (n = 6) developed mild hypotension (P < 0.001 compared with groups perfused with pancreatic enzymes only after 90 min) and increased intestinal permeability to intralumenally perfused fluorescein isothiocyanate-dextran 20 kd (P < 0.05) compared with control and enzyme-only groups, but there were no deaths. All animals perfused with both digestive enzymes and subjected to mucin disruption (n = 6) developed hypotension and increased intestinal permeability (P < 0.001 after 90 min). Pancreatic enzymes were measured in the intestinal wall of both groups subjected to mucin disruption, but not in the enzyme-only or control groups. Depletion of plasma protease inhibitors was found only in animals perfused with pancreatic enzymes plus mucin disruption, implicating increased permeability and intralumenal pancreatic enzyme egress in this group. These experiments demonstrate that increased bowel permeability via mucin disruption in the presence of pancreatic enzymes can induce shock and increase systemic protease activation in the absence of ischemia, implicating bowel mucin disruption as a key event in early ischemia. Digestive enzymes and their products, if allowed to penetrate the gut wall, may trigger multiorgan failure and death.

Pancreatic Enzyme Products: Digesting the Changes

To review the pharmacology, dosage regimens, efficacy, and safety of currently marketed pancreatic enzyme products (PEPs). Studies were identified by PubMed (1966-January 2011), clinicaltrials.gov, fda.gov, and International Pharmaceutical Abstracts. Search terms included pancreatic enzyme, lipase, Creon, Zenpep, Pancreaze, and exocrine pancreatic insufficiency (EPI). All human studies evaluating the efficacy of currently approved or potential PEPs were reviewed. PEPs are composed of porcine lipase, amylase, and protease and are used in patients with EPI secondary to cystic fibrosis, chronic pancreatitis, and pancreatectomy. In 1938, PEPs were exempted from the Food, Drug, and Cosmetic Act of 1938 and never underwent a formal Food and Drug Administration (FDA) review process. In response to reports of treatment failures during product interchange, the FDA conducted a review of available PEP products. This review found a large variability of response between the unapproved PEP products, which resulted in the FDA requiring approval of all PEP products by April 2010. The 3 delayed-release, enteric-coated PEPs currently approved by the FDA (Creon, Zenpep, and Pancreaze) have demonstrated efficacy and safety in EPI secondary to cystic fibrosis. Creon has also demonstrated safety and efficacy in EPI secondary to chronic pancreatitis and pancreatectomy. Cost difference between the 3 products is minimal. Treatment-related adverse events in clinical studies for all PEPs were less than or similar to those with placebo. At this time, Creon is an appropriate first-line agent, as it has been approved for chronic pancreatitis, pancreatectomy, and cystic fibrosis.

Pancreatic Enzyme Products: What’s New?

A healthy pancreas produces the enzymes lipase, protease, and amylase that assist in the cleaving of food particles and the absorption of nutrients. Patients with pancreatic insufficiency, commonly seen in the cystic fibrosis (CF) population, are unable to produce these enzymes endogenously. Standard treatment for pancreatic insufficiency is pancreatic enzyme replacement therapy administered by mouth. Most endogenous enzymes were developed prior to the Federal Food, Drug, and Cosmetic Act of 1938. As a result, they were marketed by companies and used by patients without the thorough investigation of the Food and Drug Administration (FDA). Enzyme manufacturers were given a deadline of April 28, 2010, by the FDA to conduct safety and efficacy studies and to submit New Drug Applications. Currently, there are only 3 FDA-approved enzyme products on the market: Creon, Zenpep, and Pancreaze. This article discusses the changes to pancreatic enzyme products over the past year and the challenges that CF practitioners have faced as a result of the changes.

Pancreatic Enzyme Products

A recent Food and Drug Administration regulation has resulted in the availability of 3 new standardized pancreatic enzyme products with proven short-term efficacy and safety (Creon®, Pancreaze®, and Zenpep®). They comply with modern chemistry, manufacturing, and control criteria, including predictable amounts of enzyme content. However, they differ in available strengths, are not designated by Food and Drug Administration as therapeutically equivalent, and are not interchangeable by pharmacists without previous approval of the prescriber.

First FDA-Approved Pancreatic Enzyme Products

First FDA-Approved Pancreatic Enzyme Products

Pancrelipase for pancreatic disorders: An update

Pancrelipase is a porcine pancreatic extract which contains the digestive enzymes lipases, proteases and amylases. In patients with pancreatic exocrine insufficiency (PEI) from conditions such as chronic pancreatitis, pancreatectomy and cystic fibrosis, pancrelipase can be used as pancreatic enzyme replacement therapy (PERT). Pancrelipase can reverse steatorrhea, prevent weight loss, control pain and correct other nutritional deficiencies resulting from exocrine insufficiency. Various forms of pancreatic enzymes were being marketed as over-the-counter medications prior to the recent FDA declaration that all pancreatic enzyme products had to obtain approval as new drugs before marketing. On the basis of evidence from recent randomized controlled trials, three pancrelipase formulations (Creon®, Zenpep® and Pancreaze®) have been approved by the FDA as effective treatments for PEI. Although several tests exist for the detection of PEI, early diagnosis still remains a challenge. Individualization of the timing of treatment initiation and dosage requirements is needed to achieve optimal effectiveness. When used at recommended doses, pancrelipase is a safe medication. Appropriate use of pancrelipase in patients with pancreatic exocrine insufficiency can achieve symptomatic relief, prevent morbidity/mortality and also improve quality of life.

Alternate Administration Options for Pancreatic Enzyme Products (PEPS): Foods on Which PEPS Can Be Administered

Attendees will learn what commercially available foods, and even homemade recipes, can be effectively used as alternatives for administering pancreatic enzyme products (PEPs).

Pancreatic Enzyme Replacement Product, Pancrelipase, Gains Federal Approval

The US Food and Drug Administration (FDA) announced on May 7, 2009, the approval of pancrelipase (Creon), a pancreatic enzyme replacement product designed to help patients with cystic fibrosis or exocrine pancreatic insufficiency digest and absorb nutrients from foods. Pancrelipase is the first FDA-approved, delayed-release pancreatic enzyme replacement product to be marketed in the United States as a result of the agency's unapproved drugs initiative. Pancrelipase, which contains a mixture of digestive enzymes extracted from the pancreas of pigs, helps patients lacking the required enzymes to digest fats, proteins, and sugars from food. Pancrelipase is approved for use in both pediatric and adult patients.The FDA had required the manufacturer of pancrelipase to submit, and the agency has approved, a Risk Evaluation and Mitigation Strategy, which includes a Medication Guide, to advise patients on the risks associated with high doses of pancrelipase, and the theoretical risk of transmission of viral disease from pigs to patients. The agency cautions that fibrosing colonopathy can result from high-dose use of pancrelipase. However, the risk may be reduced through adherence to dosing instructions in the labeling.“The risks of a rare bowel disorder and viral transmission described in the Medication Guide are considered to be risks related to all porcine-derived pancreatic enzyme products, including pancrelipase,” the FDA states. “Instructions for dosing based on weight and age should be followed carefully. Creon may be sprinkled on food. Because Creon is a delayed-release drug, patients should never crush or chew the capsule as this would cause an early release of the enzymes and a reduction in enzyme activity.”“The approval of Creon will allow patients to have access to an approved pancreatic enzyme replacement product that meets FDA standards for effectiveness, safety, and manufacturing consistency,” said Donna Griebel, MD, director, Division of Gastroenterology Products within FDA's Center for Drug Evaluation and Research (CDER).The FDA's Office of Compliance and Office of New Drugs within CDER worked with pancrelipase's manufacturer, Solvay Pharmaceuticals, through the agency's unapproved drugs initiative to help the company become compliant with federal laws by obtaining FDA approval. The agency continues to encourage the manufacturers of all other unapproved pancreatic enzyme products (PEPs) to work with the agency to obtain market approval. All PEPs must obtain FDA approval by April 28, 2010, or be removed from the marketplace.For more information on pancrelipase: http://www.fda.gov/cder/drug/infopage/pancrelipase/QA.htm. The US Food and Drug Administration (FDA) announced on May 7, 2009, the approval of pancrelipase (Creon), a pancreatic enzyme replacement product designed to help patients with cystic fibrosis or exocrine pancreatic insufficiency digest and absorb nutrients from foods. Pancrelipase is the first FDA-approved, delayed-release pancreatic enzyme replacement product to be marketed in the United States as a result of the agency's unapproved drugs initiative. Pancrelipase, which contains a mixture of digestive enzymes extracted from the pancreas of pigs, helps patients lacking the required enzymes to digest fats, proteins, and sugars from food. Pancrelipase is approved for use in both pediatric and adult patients. The FDA had required the manufacturer of pancrelipase to submit, and the agency has approved, a Risk Evaluation and Mitigation Strategy, which includes a Medication Guide, to advise patients on the risks associated with high doses of pancrelipase, and the theoretical risk of transmission of viral disease from pigs to patients. The agency cautions that fibrosing colonopathy can result from high-dose use of pancrelipase. However, the risk may be reduced through adherence to dosing instructions in the labeling. “The risks of a rare bowel disorder and viral transmission described in the Medication Guide are considered to be risks related to all porcine-derived pancreatic enzyme products, including pancrelipase,” the FDA states. “Instructions for dosing based on weight and age should be followed carefully. Creon may be sprinkled on food. Because Creon is a delayed-release drug, patients should never crush or chew the capsule as this would cause an early release of the enzymes and a reduction in enzyme activity.” “The approval of Creon will allow patients to have access to an approved pancreatic enzyme replacement product that meets FDA standards for effectiveness, safety, and manufacturing consistency,” said Donna Griebel, MD, director, Division of Gastroenterology Products within FDA's Center for Drug Evaluation and Research (CDER). The FDA's Office of Compliance and Office of New Drugs within CDER worked with pancrelipase's manufacturer, Solvay Pharmaceuticals, through the agency's unapproved drugs initiative to help the company become compliant with federal laws by obtaining FDA approval. The agency continues to encourage the manufacturers of all other unapproved pancreatic enzyme products (PEPs) to work with the agency to obtain market approval. All PEPs must obtain FDA approval by April 28, 2010, or be removed from the marketplace. For more information on pancrelipase: http://www.fda.gov/cder/drug/infopage/pancrelipase/QA.htm.

First FDA-approved pancrelipase product may mark new era for providers, patients

FDA’s recent approval of a reformulated version of Solvay Pharmaceutical Inc.’s delayed-release pancrelipase product, Creon, gives pharmacists who are active in the cystic fibrosis community something new—a pancreatic enzyme product that has passed regulatory muster. Solvay expects the new Creon formulation to be available later this year. The product is indicated for the treatment of children and adults with exocrine pancreatic insufficiency caused by cystic fibrosis or other conditions. The delayed-release oral formulation is designed to release lipase, protease, and amylase in the small intestine instead of the acidic environment of the stomach, which degrades pancreatic enzymes, according to FDA. Only one other pancrelipase product has ever gained FDA approval—Organon’s Cotazym, an immediate-release pancrelipase product that was approved by FDA in 1996 but is not currently marketed, according to the agency. Pancreatic enzyme products have been available in the United States since before the 1938 passage of the Food, Drug, and Cosmetic Act. FDA in 2004 declared pancreatic enzyme products new drugs that required formal agency approval. The agency has given manufacturers until April 2010 to obtain marketing approval of their pancrelipase products.

Pancreatic enzyme-replacement therapy in CF: considerations for the USA

Pancreatic enzyme products (PEPs) have been commercially available since before the passage of the Food, Drug and Cosmetic Act in 1938. They are a vital therapy for patients with cystic fibrosis and exocrine pancreatic insufficiency. PEPs help to enhance absorption of nutrients and thereby play an important role in maintaining good nutritional status and preserving lung function. The benefits of these supplements are not limited to cystic fibrosis and also extend to patients with other conditions, such as chronic pancreatitis. Concerns over the safety and consistency of PEPs have led to the requirement that all PEPs be approved by the US FDA. Clinical studies are currently underway to demonstrate the safety and efficacy of different PEPs, including new formulations that meet FDA guidelines for no enzyme overfill. This review highlights currently available PEPs and new formulations that hold promise for patients with exocrine pancreatic insufficiency.

In Vitro Comparison of Physical Parameters, Enzyme Activity, Acid Resistance, and pH Dissolution Characteristics of Enteric-Coated Pancreatic Enzyme Preparations: Implications for Clinical Variability and Pharmacy Substitution.

OBJECTIVE Pancreatic enzyme products were available before the 1938 passage of the Federal Food, Drug, and Cosmetic Act and have to date been marketed without required safety and efficacy testing. Despite a lack of demonstrated bioequivalence, they are often substituted for each other without physician or patient consent or monitoring. We investigated the in vitro variability of key performance parameters among a representative group of currently available pancreatic enzyme formulations.MATERIALS AND METHODS Three "branded" preparations (Creon 20 Minimicrospheres, Pancrease MT 20, Ultrase MT 20) and 3 "generic" formulations (Pangestyme CN-20, Pancrelipase 20,000 URL, and Lipram CR 20) were evaluated in vitro for physical parameters of the capsules, actual vs. labeled enzyme activity, resistance of the enteric coating to simulated gastric acid, and kinetics of simulated duodenal lipase release. All products were labeled as providing 20,000 units of lipase activity per capsule.RESULTS All products varied considerably in the percentage relationship between actual and labeled lipase activity. Actual lipase activity exceeded 165% of the label claim in 4 batches of the Pangestyme product and 1 batch of the Lipram product. All batches of the Creon, Lipram, Ultrase, and Pancrease products were found to have residual lipase activity above 80% of their baseline measurements after testing in simulated gastric acid; residual lipase activity varied significantly among batches of the Pangestyme product and was only 1% for the Pancrelipase product. The Creon and Lipram products demonstrated effective protection by the enteric coating at pH <6.0 and rapid release of enzymatic activity at pH ≥6.0. The Pangestyme and Pancrelipase products showed substantial activity of released enzymes already at pH 5.0. Release kinetics were inconsistent between batches for the Ultrase and Pancrease products.CONCLUSION This study confirms the existence of "branded"-to-"generic," product-to-product, and batch-to-batch variability among representative pancreatic enzyme formulations with pharmaceutically equivalent labels. The results confirm current cautions regarding pharmacy substitution of pancreatic enzyme products and support the announcement by the US Food and Drug Administration, made subsequent to this study, that as of April 2008 approved new drug applications will be required in order to ensure the quality, potency, and stability of these products.

Safety and Preliminary Clinical Activity of a Novel Pancreatic Enzyme Preparation in Pancreatic Insufficient Cystic Fibrosis Patients

Currently available pancreatic enzyme products are crude porcine products with few data available regarding their efficacy, safety, and manufacture. We conducted a phase 1 study of a novel pancreatic enzyme product, TheraCLEC-Total (TCT), a proprietary formulation of microbial-derived lipase, protease, and amylase, to determine its safety and preliminary efficacy in cystic fibrosis. We conducted an open-label, dose-ranging study in 23 subjects diagnosed with pancreatic insufficiency with cystic fibrosis. The subjects received TCT containing lipase dose of 100, 500, 1000, 2500, or 5000 USP U/kg per meal with each meal or snack for 3 days. The clinical and laboratory parameters and adverse events (AEs) were monitored. There were no serious AEs. Most AEs were mild, although gastrointestinal complaints were common. TCT increased the coefficient of fat and nitrogen absorption in all groups except in the low-dose group. At the other dosing levels, the mean coefficient of fat and nitrogen absorption increases were 19.1% +/- 24.9% and 17.8% +/- 13.6%, respectively, whereas the mean stool weight decreased by 517 +/- 362 g. TCT was well tolerated in this short-term exposure study. The preliminary efficacy data demonstrate lipase and protease activity with little difference seen with lipase doses greater than 500 USP U/kg per meal. These data support a larger randomized phase 2 trial.

Enzyme Content and Acid Stability of Enteric-Coated Pancreatic Enzyme Products In Vitro

Pancreatic enzymes are prescribed routinely for pancreatic insufficiency. In the current health care environment, drug substitution is commonly performed although there is no proof of therapeutic or bioequivalence for these products. The purpose of this in vitro, prospective study was to evaluate the enzyme contents and dissolution of various capsules of pancreatic enzyme using current United States Pharmacopoeia (USP) methodology. Nine different pancreatic enzyme products were purchased on the market and supplied to Irvine Analytical Laboratories (IAL) (Irvine, CA). All test products were maintained in the laboratory environment, at room temperature, throughout the testing period by IAL. USP procedures for assay and dissolution testing of pancrelipase delayed-release capsules, as described in the latest USP supplement were observed during product testing, including determination of amylase, lipase, and protease activity. In addition, a point assay with measurement of lipase after dissolution in simulated gastric fluid pH of 1.0 for 1 hour and then dissolution in pH 6 phosphate buffer for 30 minutes performed in accordance with USP guidelines. Assay results of amylase, protease, and lipase from the 9 tested products are within USP specified limits. The percentage of label claim for these enzymes was higher than depicted in their label except for one drug batch. However, the percentage of lipase activity after dissolution varied with 2 of 3 batches of 1 drug not dissolving, and 1 batch of another drug, revealing only 8% lipase activity in the USP dissolution test. While assay of pancreatic enzymes reveal they were equal to their USP claims regarding their enzyme content, not all pancreatic enzyme replacements are equal in their release of lipase activity according to USP requirements. The findings maybe clinically seen with therapeutic failures of enzyme products. The FDA has recently decreed that all pancreatic enzyme products will require an approved NDA as differences in pharmaceutical quality have been identified in this product. Thus, it is considered that substitution of these products maybe questionable. Things are seldom what they seem- not all pancreatic enzyme replacements are equal. Further studies are warranted to investigate dissolution characteristics.