Creon 10000 Mechanism of Action

Pharmacotherapeutic group: Digestion products, multi-enzymes. ATC code: A09AA02.
Pharmacology: Pharmacodynamics: Creon 10000 capsules contain pancreatin powder produced from porcine pancreas tissue in the form of gastro-resistant pellets in hard gelatin capsules.
Pancreatin contains the excretory pancreatic enzymes lipase, alpha-amylase, trypsin, chymotrypsin and other enzymes. Pancreatin also contains additional excipients devoid of enzymatic activity. The non-absorbed portion is broken down and denatured by gastric juices or bacteria. Gastrointestinal availability is determined by enzyme activity and the pharmaceutical form. Lipase enzyme activity and trypsin content are crucial whereas amylolytic activity is significant only in the treatment of cystic fibrosis since food polysaccharides continue to be broken down undisturbed even in cases of chronic pancreatitis.
Pancreatic lipase breaks down the fatty acids in positions 1 and 3 from a triacylglyceride molecule. The free fatty acids and 2-monoglycerides thus released are mainly rapidly absorbed from the upper small intestine with the aid of bile acids. Animal pancreatic lipase is unstable in acids, just like human lipase. Its lipolytic activity is therefore inactivated to an increasingly irreversible extent at pH <4.
Trypsin is activated from trypsinogen autocatalytically or by small intestine enterokinase, and is broken down as endopeptidase peptide compounds involving lysine and arginine. Based on recent research, trypsin-mediated feedback inhibition of stimulated pancreatic secretion by active trypsin in the upper small intestine is assumed. The analgesic effect of pancreatin preparations described in a few studies is attributed to this effect.
Alpha-amylase very rapidly breaks down glucose-containing polysaccharides as endoamylase such that its activity is still sufficient even in cases where the secretory activity of the pancreas is considerably reduced due to disease.
The galenical principle of Creon guarantees optimum use of the enzymatic activities of pancreatin for the digestion of food. The gastro-resistant micropellets containing a mixture of all the pancreatic enzymes are enclosed in readily soluble hard gelatine capsules. The capsules dissolve within 2 to 3 minutes in the stomach, regardless of pH, and release numerous micropellets. This multi-dosing principle has been developed in order to mix the micropellets thoroughly with the chyme. This facilitates the entire removal of the micropellets with the chyme from the stomach to the duodenum and effective distribution of the enzymes in the chyme post-release. As soon as the micropellets reach the small intestine, the protective film quickly dissolves (at pH >5.5) and the enzymes are released. The breakdown of the chyme can then begin as in the physiological digestion process since the breaking down and absorption of nutrients is limited in terms of time and space. The degradation products are either absorbed directly or further hydrolysed by intestinal enzymes.
Due to the galenical preparation, activity losses are avoided with Creon due to a strongly acidic gastric pH. Enzyme availability is pH-dependent.
Clinical efficacy: Overall, 30 studies have been carried out to establish the clinical efficacy of Creon in patients with exocrine pancreatic insufficiency. These include 10 studies versus placebo involving patients with cystic fibrosis, chronic pancreatitis or following surgery.
In all randomised, placebo-controlled efficacy studies, the primary objective was to demonstrate the superiority of Creon over placebo for the primary efficacy parameter, the fat absorption coefficient (CFA). The CFA refers to the percentage of fat absorbed in relation to the total fat intake.
In PEI studies versus placebo, the mean CFA during Creon treatment was higher than that observed with placebo (83% versus 62.6%). In all trials, regardless of design, the mean CFA value at the end of Creon treatment was comparable to that recorded in the placebo-controlled studies.
Creon treatment substantially improves the symptoms of exocrine pancreatic insufficiency including stool consistency, abdominal pain, distension and bowel movements, regardless of the underlying condition.
Paediatric population: The efficacy of Creon in cystic fibrosis was confirmed in 288 paediatric patients ranging from new-born infants to adulthood. In all studies, the mean CFA value on completion of Creon treatment was over 80%, regardless of age group.
Pharmacokinetics: Since animal studies have not highlighted intact enzyme absorption, no conventional pharmacokinetic studies were carried out. Pancreatic enzymes do not have to be absorbed in order to be effective. However, their full therapeutic activity is apparent in the intestinal lumen. As proteins, pancreatic enzymes are mainly digested in the intestine by autolysis or proteolysis as they pass through the gastrointestinal tract and are absorbed as peptides and amino acids.
Toxicology: Preclinical safety data: There is no evidence of relevant acute, subchronic or chronic toxicity in the preclinical data. No genotoxicity, carcinogenicity or reproduction toxicity studies have been conducted. Pancreatin is not expected to have systemic toxic effects following oral administration.