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.
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。