2003D-0206 - Draft Guidance for Industry on Exocrine Pancreatic Insufficiency Drug Products--Submitting New Drug Application; Availability
FDA Comment Number : EC10
Submitter : Dr. Tibor Sipos Date & Time: 07/12/2004 12:07:04
Organization : Digestive Care, Inc.
Drug Industry
Category :
Issue Areas/Comments
GENERAL
GENERAL
PART 7 OF 10
COMMENTS SUBMITTED BY DIGESTIVE CARE, INC. (1120 WIN DRIVE, BETHLEHEM, PA 18017)
DOCKET NO. 2003D-0206 (2003N-0205)

NON-CLINICAL PHARMACOLOGY AND TOXICOLOGY:
We concur with FDA's position that no new non-clinical studies are required for products which have been safety and effectively used in patients for some 50 years.

Human Pharmacokinetics and Bioavailability Section:
- Pharmacokinetics intubation studies are very difficult to perform in the intestinal milieu
- Intubation studies in children are technically more difficult than in adults
- Safety and efficacy in clinical studies should be sufficient.

The demonstration of bioavailability of the exogenously administered pancreatic enzymes in the intestine requires intubation with a multi-lumen gastrointestinal tube and the aspiration of the gastrointestinal contents for subsequent in vitro analysis of the enzymes for biological activity. The majority of the intubations have been carried out with adult patients in the fasting state and by employing a triple-lumen gastrointestinal tube under fluoroscopic guidance. One lumen is positioned in the stomach to aspirate out the gastric juice from the stomach while the second and third lumens are positioned in the duodenum and the upper intestine 10-20 cm from the ligament of Treitz, respectively. The procedure to position the lumens usually takes 35-45 minutes under optimal conditions. Since the gastrointestinal tube is rubbed against the gastrointestinal mucosa with every swallowing of saliva, it causes stimulation of the gastrointestinal mucosa that, in turn, releases endogenous hormones to prompt the release of secretin and cholecystokinin (CCK) into the blood stream. The released secretin/CCK, in turn, activates the pancreas to release some preformed enzymes into the duodenum. Collections of the duodenal juices over a 30-60 minute period usually provide sufficient volume of pancreatic secretion to establish baseline collection levels. Infusion of a bolus dose of exogenously administered secretin/CCK is administered to deplete the pancreatic reserves from all pre-synthesized and stored enzymes. Collection over a 60-90 minute period yields maximum enzyme levels in the initial 15-45 minute stimulation period, followed by a precipitous drop of enzyme secretion and the establishment of pre-hormone stimulated conditions. At this point five (5) pancrelipase capsules are administered to the patient with a glass of water, followed by additional liquid or a test meal to simulate ingestion of a meal. The gastric lumen is clamped to prevent aspiration of the gastric content while the duodenal and the upper intestinal lumen are aspirated to collect the intestinal contents for in vitro analysis of the released active enzymes from the exogenously administered capsules for the next two hours. The results showed that some of the enzymes are released in the duodenum and greater amounts of the enzymes are released in the jejunum or further down the intestine. A total of four to five hours are required to achieve desirable collection conditions and obtain sufficient quantity of samples for the in vitro enzyme assays.

Recently a seven lumen gastrointestinal tube was developed to reach even further down the intestine to obtain samples from the upper (duodenum), middle (jejunum) and lower (ileum) intestine. Three (3) adult cystic fibrosis patients were intubated with the seven lumen gastrointestinal tube and marker perfusion technique (Butt AM, et. al., 14th NASPGN Meeting, Orlando, Florida, 2001). Intestinal samples aspirated over seven and a half (7 1/2) hours were analyzed for enzyme activities, pH markers and bile acids. Studies with one of the commercially-marketed, enteric-coated formulation showed that the exogenously administered pancrelipase was mostly released in the jejunum (1-2.5 hours) and ileum.