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

Abstract

AbstractBackgroundEnteral 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.MethodsTwenty 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.ResultsBoth 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).ConclusionIn 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.