Use of a Mutilumen Catheter to Assess the Bioavailability of an Enteric- Coated High-Buffered Pancrelipase Formulation in Patients with Exocrine Pancreatic Insufficiency

Abstract

IntroductionPancreatic enzyme products (PEPs) have been in use for decades to treat patients with deficient production of pancreatic digestive enzymes, a condition known as exocrine pancreatic insufficiency (EPI). Patients suffering from EPI are unable to produce sufficient pancreatic enzymes of their own to aid digestion. In adults with EPI secondary to acute/chronic pancreatitis or pancreatic cancer, this leads to steatorrhea and weight-loss. In children with EPI secondary to cystic fibrosis or Shwachman-Diamond Syndrome, this condition can also result in malabsorption with subsequent growth and developmentrelated disorders [1].Since most PEPs are specially formulated from porcine pancreas, considerable differences in enzyme activity are to be expected from different manufacturers and from batch to batch. The development of fibrosing colonopathy has been linked to administration of high potency (>20,000 USP units of lipase/capsule) and high dose pancreatic enzyme replacement therapy over time [2,3]. Substitution between branded and generic PEPs resulted in therapeutic failure [4,5]. The enzymes contained in these products are prone to inactivation if the gastrointestinal pH is not within the optimum pH range (e.g. pancreatic lipase is irreversibly inactivated in the acidic pH of the stomach). In one instance, failure of the enteric coating resulted in withdrawal of a product from the market [6]. Deficient bicarbonate secretion in patients with pancreatic insufficiency results in insufficient neutralization of bile acids in the upper intestine, which can increase the risk of enzyme inactivation in the duodenum if the PEP is formulated without a buffering agent. PEPs from different manufacturers are, therefore, not pharmaceutical equivalents, and inappropriate substitution in the absence of bioavailability studies may lead to overdosing, which can have serious consequences resulting in AbstractTreatment of exocrine pancreatic insufficiency (EPI) secondary to conditions including cystic fibrosis or chronic pancreatitis requires exogenous supplementation with a specially formulated pancreatic enzyme product (PEP). The FDA has mandated that the intestinal bioavailability of these preparations be evaluated in vivo in patients.This pilot clinical study examined the feasibility of using a multi-lumen catheter with an occluding balloon to measure changes in intraduodenal enzyme concentrations following oral administration of a PEP.In this two arm cross-over study, patients with mild-severe EPI were administered enteric coated (EC) highbuffered pancrelipase or placebo capsules with a liquid Lundh meal. Gastric and duodenal samples were aspirated at 15-minute intervals over 3 hours in each treatment arm. The concentrations of three pancreatic enzymes (lipase, amylase, and protease) were measured in the collected fluids. The maximum concentration (C max ), and area under the duodenal enzyme concentration vs. time profile (AUC) were determined.Comparison of enzyme concentrations between placebo and treatment phases demons...

Analysis of Pharmacokinetic & Pharmacodynamic Models in Oral and Transdermal Dosage Forms

“…"Flurbiprofen" is a non-selective cyclo-oxygenase inhibitor and member of a series of alkanoic acid derivatives and has shown to have anti-inflammatory and analgesic activity. Flurbiprofen has also caused a dose dependent inhibition of collagen-induced platelet aggregation in patients with platelet-rich plasma [34].…”