The primary action of ChiRhoStim® is to increase the volume and bicarbonate content of secreted pancreatic juices. The standard unit of activity used for ChiRhoStim® is the clinical unit as defined in the literature.⁽⁵⁾ Synthetic human secretin (sHS), synthetic porcine secretin (sPS) and biologically derived porcine secretin (bPS) have been evaluated and compared in the validated cat bioassay used for release of bPS. sHS and sPS were found to have similar pharmacological activity in terms of stimulating the exocrine pancreas to secrete juice and bicarbonate. The potency correlation with bPS for both sHS and sPS was 0.2 mcg (sHS or sPS) corresponding to 1 CU (bPS). The biological activity of sHS and sPS was approximately 5.0 CU per mcg as opposed to 3.0 CU per mcg for bPS.

Mechanism of Action

Secretin is a hormone that is normally released from the duodenum upon exposure of the proximal intestinal lumen to gastric acid, fatty acids and amino acids. Secretin is released from enterochromaffin cells in the intestinal mucosa. Secretin receptors have been identified in the pancreas, stomach, liver, colon and other tissues. When secretin binds to secretin receptors on pancreatic duct cells it opens cystic fibrosis transmembrane conductance regulator (CFTR) channels, leading to secretion of bicarbonate-rich-pancreatic fluid. Secretin may also work through vagal-vagal neural pathways since stimulation of the efferent vagus nerve stimulates bicarbonate secretion and atropine blocks secretin-stimulated pancreatic secretion. See references 6 and 7 for additional details on mechanism of action of secretin and feedback controls.

Pharmacokinetics

The PK profile for synthetic human secretin was evaluated in 12 normal subjects. After intravenous bolus administration of 0.4 mcg/kg, synthetic human secretin concentration rapidly declines to baseline secretin levels within 90 to 120 minutes. The elimination half-life of synthetic human secretin is 45 minutes. The clearance of synthetic human secretin is 580.9 ± 51.3 mL/min and the volume of distribution is 2.7 L.

Animal Toxicology and/or Pharmacology

A single intravenous dose of synthetic human secretin at 20 mcg/kg was not lethal to mice or rabbits.

Clinical Studies

Stimulation of pancreatic secretions, including bicarbonate to aid in the diagnosis of Exocrine Pancreas Dysfunction:

ChiRhoStim® administered intravenously stimulates the exocrine pancreas to secrete pancreatic juice, which can assist in the diagnosis of exocrine pancreas dysfunction. Normal ranges for pancreatic secretory response to intravenous secretin in patients with defined pancreatic disease have been shown to vary. One source of variation is related to the inter-investigator differences in operative technique.

In two crossover studies (CRC98-2 and CRC99-9), a total of 18 patients with a documented history of chronic pancreatitis were given sHS, sPS and bPS. The results appear in Figures 1 and 2. In another study, 35 normal volunteers were given sHS. The results appear in Figures 1 and 2.

FIGURE 1

FIGURE 2

The values obtained for Figures 1 and 2 were performed by investigators skilled in performing secretin stimulation testing and are to be taken only as guidelines. These results should not be generalized to results of secretin stimulation testing conducted in other laboratories. However, a volume response of less than 2 mL/kg/hr, bicarbonate concentration of less than 80 mEq/L, and a bicarbonate output of less than 0.2 mEq/kg/hr are consistent with impaired pancreatic function.

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