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Abstract：
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.
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.
摘要：
背景：由于不可预测的吸收，在短肠综合征合并肠衰竭（SBS-IF）中，肠内药物治疗具有挑战性。SEFA-6179是一种肠内给药的中链脂肪酸类似物，正在开发用于肠衰竭相关的肝病。我们研究了两种SEFA-6179制剂在两种大型SBS-IF动物模型中的药代动力学。包括一个新的假空肠造口术模型.
方法:获得20只尤卡坦小型猪。一半接受了单剂量SEFA-6179给药的切除前药代动力学研究。然后所有小型猪接受了90%的空肠切除，空肠吻合术或腹膜内结肠旁路吻合术与直肠近端吻合（假空肠吻合术）。在术后第3天,进行单剂量药代动力学研究。
结果：两种SBS-IF模型均耐受良好。与空肠小型猪相比，假空肠吻合术小型猪在术后第4天具有更严重的吸收不良表型，体重减轻（0.1vs.-0.9kg,P=0.03）和液体腹泻（布里斯托尔5vs.Bristol7，P=0.0007）。与切除前小型猪相比，空肠和假空肠吻合术小型猪的SEFA-6179的总血浆暴露量均较低（空肠：减少37％，P=0.049；假空肠吻合术：减少74%，P=0.0001)。与切除前相比，假空肠造口术组的血浆峰值浓度也较低（减少了65％，P=0.04),空肠回肠组没有（P=0.47）。
结论：在两个SBS-IF小型猪模型中，与切除前小型猪相比,SEFA-6179具有显著降低的吸收。可能需要针对不同肠解剖结构和功能的剂量优化。我们描述了一种新的SBS-IF假空肠造口术模型，该模型可能会改善临床前研究对肠造口术的SBS-IF患者的转化。本文受版权保护。保留所有权利。
方法:获得20只尤卡坦小型猪。一半接受了单剂量SEFA-6179给药的切除前药代动力学研究。然后所有小型猪接受了90%的空肠切除，空肠吻合术或腹膜内结肠旁路吻合术与直肠近端吻合（假空肠吻合术）。在术后第3天,进行单剂量药代动力学研究。
结果：两种SBS-IF模型均耐受良好。与空肠小型猪相比，假空肠吻合术小型猪在术后第4天具有更严重的吸收不良表型，体重减轻（0.1vs.-0.9kg,P=0.03）和液体腹泻（布里斯托尔5vs.Bristol7，P=0.0007）。与切除前小型猪相比，空肠和假空肠吻合术小型猪的SEFA-6179的总血浆暴露量均较低（空肠：减少37％，P=0.049；假空肠吻合术：减少74%，P=0.0001)。与切除前相比，假空肠造口术组的血浆峰值浓度也较低（减少了65％，P=0.04),空肠回肠组没有（P=0.47）。
结论：在两个SBS-IF小型猪模型中，与切除前小型猪相比,SEFA-6179具有显著降低的吸收。可能需要针对不同肠解剖结构和功能的剂量优化。我们描述了一种新的SBS-IF假空肠造口术模型，该模型可能会改善临床前研究对肠造口术的SBS-IF患者的转化。本文受版权保护。保留所有权利。
