Absorption of an engineered medium-chain fatty acid analogue in two short bowel syndrome minipig models

• Published in: JPEN. Journal of parenteral and enteral nutrition Vol. 47; no. 8; p. 1028
• Main Authors: Fligor, Scott C, Tsikis, Savas T, Hirsch, Thomas I, Pan, Amy, Mitchell, Paul D, Quigley, Mikayla, Carbeau, Sarah, Nedder, Arthur, Gura, Kathleen M, Puder, Mark
• Format: Journal Article
• Language: English
• Published: United States 01.11.2023
• Subjects: Animals; Disease Models, Animal; Fatty Acids; Humans; Intestinal Diseases; Intestinal Failure; Intestines; Short Bowel Syndrome - drug therapy; Short Bowel Syndrome - surgery; Swine; Swine, Miniature; swine; intestinal failure; pharmacokinetics; animal; disease models; jejunostomy; short bowel syndrome
• ISSN: 1941-2444
• DOI: 10.1002/jpen.2563

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. 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. 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). 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.