Oral delivery of the anti-tumor necrosis factor α domain antibody, V565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus monkeys.

Autor: Crowe JS; a VHsquared Ltd. , Babraham , UK.; b VHsquared Ltd., Wellcome Sanger Institute , Hinxton , UK., Roberts KJ; b VHsquared Ltd., Wellcome Sanger Institute , Hinxton , UK., Carlton TM; b VHsquared Ltd., Wellcome Sanger Institute , Hinxton , UK., Maggiore L; b VHsquared Ltd., Wellcome Sanger Institute , Hinxton , UK., Cubitt MF; b VHsquared Ltd., Wellcome Sanger Institute , Hinxton , UK., Ray KP; a VHsquared Ltd. , Babraham , UK., Donnelly MC; a VHsquared Ltd. , Babraham , UK., Wahlich JC; a VHsquared Ltd. , Babraham , UK., Humphreys JI; a VHsquared Ltd. , Babraham , UK., Robinson JR; a VHsquared Ltd. , Babraham , UK., Whale GA; a VHsquared Ltd. , Babraham , UK., West MR; b VHsquared Ltd., Wellcome Sanger Institute , Hinxton , UK.
Jazyk: angličtina
Zdroj: Drug development and industrial pharmacy [Drug Dev Ind Pharm] 2019 Mar; Vol. 45 (3), pp. 387-394. Date of Electronic Publication: 2018 Nov 25.
DOI: 10.1080/03639045.2018.1542708
Abstrakt: Objective: V565 is a novel oral anti-tumor necrosis factor (TNF)-α domain antibody being developed for topical treatment of inflammatory bowel disease (IBD) patients. Protein engineering rendered the molecule resistant to intestinal proteases. Here we investigate the formulation of V565 required to provide gastro-protection and enable optimal delivery to the lower intestinal tract in monkeys.
Methods: Enteric-coated V565 mini-tablets were prepared and dissolution characteristics tested in vitro. Oral dosing of monkeys with enteric-coated mini-tablets containing V565 and methylene blue dye enabled in vivo localization of mini-tablet dissolution. V565 distribution in luminal contents and feces was measured by enzyme-linked immunosorbent assay (ELISA). To mimic transit across the damaged intestinal epithelium seen in IBD patients an intravenous (i.v.) bolus of V565 was given to monkeys and pharmacokinetic parameters of V565 measured in serum and urine by ELISA.
Results: Enteric-coated mini-tablets resisted dissolution in 0.1 M HCl, before dissolving in a sustained release fashion at neutral pH. In orally dosed monkeys methylene blue intestinal staining indicated the jejunum and ileum as sites for mini-tablet dissolution. Measurements of V565 in monkey feces confirmed V565 survival through the intestinal tract. Systemic exposure after oral dosing was very low consistent with limited V565 mucosal penetration in healthy monkeys. The rapid clearance of V565 after i.v. dosing was consistent with renal excretion as the primary route for elimination of any V565 reaching the circulation.
Conclusions: These results suggest that mini-tablets with a 24% Eudragit enteric coating are suitable for targeted release of orally delivered V565 in the intestine for topical treatment of IBD.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje