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

Autor: Fligor SC; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Tsikis ST; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Hirsch TI; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA., Pan A; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA., Mitchell PD; Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, Massachusetts, USA., Quigley M; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA., Carbeau S; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA., Nedder A; Animal Resources Children's Hospital, Boston Children's Hospital, Boston, Massachusetts, USA., Gura KM; Harvard Medical School, Boston, Massachusetts, USA.; Department of Pharmacy and the Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Massachusetts, USA., Puder M; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: JPEN. Journal of parenteral and enteral nutrition [JPEN J Parenter Enteral Nutr] 2023 Nov; Vol. 47 (8), pp. 1028-1037. Date of Electronic Publication: 2023 Oct 08.
DOI: 10.1002/jpen.2563
Abstrakt: 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.
(© 2023 The Authors. Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)
Databáze: MEDLINE
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