Absorption of an Engineered Medium-chain Fatty Acid Analogue in Two Short Bowel Syndrome Minipig Models

Overview

Journal JPEN J Parenter Enteral Nutr

Publisher Wiley

Specialty Nutritional Sciences

Date 2023 Sep 19

PMID 37726175

Authors

Scott C Fligor

Savas T Tsikis

Thomas I Hirsch

Amy Pan

Paul D Mitchell

Mikayla Quigley

Sarah Carbeau

Arthur Nedder

Kathleen M Gura

Mark Puder

Affiliations

Soon will be listed here.

Abstract

Background: Enteral drug therapy is challenging in short bowel syndrome with intestinal failure (SBS-IF) because of unpredictable absorption. SEFA-6179 is an enterally administered medium-chain fatty acid analogue under development for intestinal failure-associated liver disease. We investigate the pharmacokinetics of two SEFA-6179 formulations in two large-animal models of SBS-IF, including a new pseudojejunostomy model.

Methods: Twenty Yucatan minipigs were obtained. Half underwent pre-resection pharmacokinetic study with single-dose SEFA-6179 administration. All minipigs then underwent 90% jejunoileal resection, with either a jejunoileal anastomosis or bypass of the intraperitoneal colon with anastomosis just proximal to the rectum (pseudojejunostomy). On postoperative day 3, a single-dose pharmacokinetic study was performed.

Results: Both SBS-IF models were well tolerated. Compared with the jejunoileal anastomosis minipigs, pseudojejunostomy minipigs had a more severe malabsorptive phenotype with weight loss by postoperative day 4 (+0.1 vs -0.9 kg, P = 0.03) and liquid diarrhea (Bristol 5 vs Bristol 7, P = 0.0007). Compared with pre-resection minipigs, both jejunoileal and pseudojejunostomy minipigs had lower total plasma exposure of SEFA-6179 measured by area under the curve (jejunoileal: 37% less, P = 0.049; pseudojejunostomy: 74% less, P = 0.0001). Peak plasma concentration was also lower in the pseudojejunostomy group compared with pre-resection (65% less, P = 0.04), but not lower in the jejunoileal group (P = 0.47).

Conclusion: In two SBS-IF minipig models, SEFA-6179 had substantially decreased absorption compared with pre-resection minipigs. Dose optimization for different intestinal anatomy and function may be required. We describe a new SBS-IF pseudojejunostomy model that may improve the translation of preclinical research to patients with SBS-IF who have enterostomies.

References

Turner J, Wales P, Nation P, Wizzard P, Pendlebury C, Sergi C . Novel neonatal piglet models of surgical short bowel syndrome with intestinal failure. J Pediatr Gastroenterol Nutr. 2010; 52(1):9-16. DOI: 10.1097/MPG.0b013e3181f18ca0. View

Jeppesen P, Mortensen P . The influence of a preserved colon on the absorption of medium chain fat in patients with small bowel resection. Gut. 1998; 43(4):478-83. PMC: 1727269. DOI: 10.1136/gut.43.4.478. View

Porter C, Trevaskis N, Charman W . Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007; 6(3):231-48. DOI: 10.1038/nrd2197. View

Thymann T, Stoll B, Mecklenburg L, Burrin D, Vegge A, Qvist N . Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr Gastroenterol Nutr. 2014; 58(6):694-702. DOI: 10.1097/MPG.0000000000000295. View

Tappenden K . Intestinal adaptation following resection. JPEN J Parenter Enteral Nutr. 2014; 38(1 Suppl):23S-31S. DOI: 10.1177/0148607114525210. View

Aunsholt L, Thymann T, Qvist N, Sigalet D, Husby S, Sangild P . Prematurity Reduces Functional Adaptation to Intestinal Resection in Piglets. JPEN J Parenter Enteral Nutr. 2014; 39(6):668-76. DOI: 10.1177/0148607114528714. View

Fligor S, Tsikis S, Hirsch T, Pan A, Moskowitzova K, Rincon-Cruz L . A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure-Associated Liver Disease in Preterm Yorkshire Piglets. Gastroenterology. 2023; 165(3):733-745.e9. PMC: 10527514. DOI: 10.1053/j.gastro.2023.05.035. View

Mutanen A, Lohi J, Merras-Salmio L, Koivusalo A, Pakarinen M . Prediction, identification and progression of histopathological liver disease activity in children with intestinal failure. J Hepatol. 2020; 74(3):593-602. DOI: 10.1016/j.jhep.2020.09.023. View

Jeppesen P . Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. JPEN J Parenter Enteral Nutr. 2014; 38(1 Suppl):8S-13S. DOI: 10.1177/0148607114520994. View

10.

Vegge A, Thymann T, Lund P, Stoll B, Bering S, Hartmann B . Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates. Am J Physiol Gastrointest Liver Physiol. 2013; 305(4):G277-85. PMC: 4073902. DOI: 10.1152/ajpgi.00064.2013. View

11.

Gonzalez L, Moeser A, Blikslager A . Porcine models of digestive disease: the future of large animal translational research. Transl Res. 2015; 166(1):12-27. PMC: 4458388. DOI: 10.1016/j.trsl.2015.01.004. View

12.

Sangild P, Ney D, Sigalet D, Vegge A, Burrin D . Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges. Am J Physiol Gastrointest Liver Physiol. 2014; 307(12):G1147-68. PMC: 4269678. DOI: 10.1152/ajpgi.00088.2014. View

13.

Tsikis S, Fligor S, Secor J, Yu L, Pan A, Loring G . Outcomes and Perioperative Nutritional Management in a Porcine Model of Short Bowel Syndrome. J Surg Res. 2022; 274:59-67. PMC: 9038684. DOI: 10.1016/j.jss.2022.01.004. View

14.

Hong W, Tan W, Law L, Ong D, Lo E . Changes of Drug Pharmacokinetics in Patients with Short Bowel Syndrome: A Systematic Review. Eur J Drug Metab Pharmacokinet. 2021; 46(4):465-478. DOI: 10.1007/s13318-021-00696-y. View

15.

Secor J, Yu L, Tsikis S, Fligor S, Puder M, Gura K . Current strategies for managing intestinal failure-associated liver disease. Expert Opin Drug Saf. 2020; 20(3):307-320. DOI: 10.1080/14740338.2021.1867099. View

16.

Tsikis S, Fligor S, Secor J, Yu L, Pan A, MITCHELL P . An in-line digestive cartridge increases enteral fat and vitamin absorption in a porcine model of short bowel syndrome. Clin Nutr. 2022; 41(5):1093-1101. PMC: 9050916. DOI: 10.1016/j.clnu.2022.03.026. View

17.

Severijnen R, Bayat N, Bakker H, Tolboom J, Bongaerts G . Enteral drug absorption in patients with short small bowel : a review. Clin Pharmacokinet. 2004; 43(14):951-62. DOI: 10.2165/00003088-200443140-00001. View

18.

Carbonnel F, Cosnes J, Chevret S, Beaugerie L, Ngo Y, Malafosse M . The role of anatomic factors in nutritional autonomy after extensive small bowel resection. JPEN J Parenter Enteral Nutr. 1996; 20(4):275-80. DOI: 10.1177/0148607196020004275. View

19.

Goulet O, Nader E, Pigneur B, Lambe C . Short Bowel Syndrome as the Leading Cause of Intestinal Failure in Early Life: Some Insights into the Management. Pediatr Gastroenterol Hepatol Nutr. 2019; 22(4):303-329. PMC: 6629594. DOI: 10.5223/pghn.2019.22.4.303. View