Preclinical safety evaluation of calcineurin inhibitors delivered through an intraductal route to prevent post-ERCP pancreatitis demonstrates endocrine and systemic safety

Jianbo Ni; Asna Khalid; Yu-Chu Lin; Monique T Barakat; Jing Wang; Cheng-Yu Tsai; Pasha Reza Shams Azar; Ying Ding; Judy-April Murayi; Thottala Jayaraman; Ronald Poropatich; Rita Bottino; Li Wen; Georgios I Papachristou; Gayathri Swaminathan; Mang Yu; Sohail Z Husain

doi:10.1016/j.pan.2023.03.009

Preclinical safety evaluation of calcineurin inhibitors delivered through an intraductal route to prevent post-ERCP pancreatitis demonstrates endocrine and systemic safety

Pancreatology. 2023 Jun;23(4):333-340. doi: 10.1016/j.pan.2023.03.009. Epub 2023 Mar 30.

Authors

Jianbo Ni¹, Asna Khalid², Yu-Chu Lin², Monique T Barakat³, Jing Wang⁴, Cheng-Yu Tsai², Pasha Reza Shams Azar², Ying Ding⁵, Judy-April Murayi⁶, Thottala Jayaraman⁷, Ronald Poropatich⁸, Rita Bottino⁹, Li Wen¹⁰, Georgios I Papachristou¹¹, Gayathri Swaminathan², Mang Yu¹², Sohail Z Husain¹³

Affiliations

¹ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
³ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Radiology and Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
⁷ Department of Oral and Craniofacial Sciences, School of Dental Medicine, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁸ University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
⁹ Imagine Islet Center, Imagine Pharma, 1401 Forbes Avenue, Pittsburgh, PA, USA.
¹⁰ Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
¹¹ The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹² Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: yumyu@stanford.edu.
¹³ Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: sohail.husain@stanford.edu.

PMID: 37031049
DOI: 10.1016/j.pan.2023.03.009

Abstract

Objective: There is an urgent need for safe and targeted interventions to mitigate post-ERCP pancreatitis (PEP). Calcineurin inhibitors (CnIs) offer therapeutic promise as calcineurin signaling within acinar cells is a key initiating event in PEP. In previous proof-of-concept studies using experimental models, we showed that concurrent intra-pancreatic ductal administration of the CnIs, tacrolimus (Tac) or cyclosporine A (CsA) with the ERCP radiocontrast agent (RC) prevented PEP. To translate this finding clinically, we investigated potential toxic effects of intraductal delivery of a single-dose RC-CnI formulation on endocrine pancreas function and systemic toxicities in a preclinical PEP model.

Methods: C57BL/6J mice underwent ductal cannulation and received a single, intra-pancreatic ductal infusion of RC or RC with Tac or CsA (treatment groups) or underwent ductal cannulation without infusion ('sham' group). To assess endocrine function, intraperitoneal glucose tolerance test (IPGTT) was performed at two days before infusion and on day 2 and 14 post-surgery. To evaluate off-target tissue toxicities, renal and hepatic function-related parameters including blood urea nitrogen, plasma creatinine, potassium, aspartate aminotransferase, alanine aminotransferase, and total bilirubin were measured at the same time-points as IPGTT. Histological and biochemical indicators of pancreas injury and inflammation were also evaluated.

Results: No abnormalities in glucose metabolism, hepatic or renal function were observed on day 2 or 14 in mice administered with intraductal RC or RC with Tac or CsA.

Conclusion: Intraductal delivery of RC-CnI formulation was safe and well-tolerated with no significant acute or subacute endocrine or systemic toxicities, underscoring its clinical utility to prevent PEP.

Keywords: Calcineurin inhibitor; Intraductal; Post-ERCP pancreatitis; Toxicity.

MeSH terms

Animals
Calcineurin Inhibitors* / pharmacology
Calcineurin Inhibitors* / therapeutic use
Cholangiopancreatography, Endoscopic Retrograde / adverse effects
Contrast Media
Cyclosporine / therapeutic use
Mice
Mice, Inbred C57BL
Pancreatitis* / etiology
Pancreatitis* / pathology
Pancreatitis* / prevention & control
Tacrolimus / pharmacology
Tacrolimus / therapeutic use

Substances

Calcineurin Inhibitors
Tacrolimus
Cyclosporine
Contrast Media