Optimizing a Novel Intraductal Delivery of Calcineurin Inhibitors as a Radiocontrast Infusion Formulation to Prevent Post-ERCP Pancreatitis
Abstract
An endoscopic retrograde cholangiopancreatography (ERCP) is a procedure that is commonly performed to alleviate the life-threatening gastrointestinal (GI) emergency of gallstones that get stuck in the main bile duct of the liver or in certain cases to treat pancreas- and liver-related trauma. In this procedure, patients are given anesthesia for sedation, and a thin, flexible endoscope is inserted into the mouth and then gently advanced to the first part of the small intestine. A smaller tube is passed into the bile duct or pancreatic duct (PD), radiocontrast (RC) dye is injected to visualize the anatomy of the ducts, and the inciting problem is diagnosed and treated. This procedure is commonly performed in the US and has become a crucial standard of care for the above types of GI issues. A major complication of ERCP occurs in about 3 to 15 patients out of 100 undergoing the procedure, which is the development of an excruciatingly painful medical emergency called acute pancreatitis. Many patients state that pancreatitis is the most painful affliction that they have ever suffered. Pancreatitis and its complications can involve weeks of hospitalization, the need for intensive care unit support, and can lead to death. It is also sobering to know that, as physicians, in most cases we cannot reliably predict who will develop post-ERCP pancreatitis (PEP). My laboratory research group at the University of Pittsburgh recently made the discovery that a critical pathway in the development of PEP is through a molecular signaling pathway involving a protein called calcineurin (Cn). Based on a series of published studies from our group about the role of Cn in PEP, we came up with novel formulations that combine Cn inhibitors with the standalone RC. As proof-of-principle, in preliminary testing in animal models, we found that the combination products substantially prevented PEP. While many products face a long and extensive path through Food and Drug Administration (FDA) regulation, we will benefit because each of the components of the combination products is already FDA-approved for oral or intravenous use. Thus, we put together a proposal to do just enough testing of the safety and efficacy of these novel combinations for the purpose of obtaining FDA approval and subsequently launching clinical trials. Each of the experiments was strategically planned to exploit information about what we already know about the side effects of the drugs by themselves. In particular, we will test whether they carry even a minute risk of causing diabetes when instilled into the pancreas. We also put together a strategic plan with multiple partners firstly to ensure the successful completion of the proposed preclinical safety and effectiveness testing, secondly to overcome the common hurdles for initial FDA approval, and thirdly to design the necessary clinical trials to take the product to final FDA approval and thereafter to the commercial market. The partners include an expert pharmacologist, ERCP specialists, military consultants, the University of Pittsburgh’s Innovation Institute, industry partners (including a startup company and a multi-billion-dollar RC maker), a specialized facility to conduct standardized high-quality experiments (known as Good Laboratory Practice [GLP] facilities), and a regulatory consultant. We feel confident that we can safely perform ERCP procedures through use of our novel formulations. The long-term promise of this technology is that it will stimulate more innovations based on the concept that Cn inhibitors can block RC injury to organs. Depending on the results of the current preclinical proposal and subsequent human studies, we believe that the combination Cn inhibitor-RC formulations will become a new standard of care for use in ERCP because it will prevent the problem of PEP.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910683
Entities
People
- Sohail Z Husain
Organizations
- Stanford University School of Medicine
- United States Army