title: A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It.
abstract: LB30870, a new direct thrombin inhibitor, showed 80% reduction in oral bioavailability in fed state. The present study aims to propose trypsin binding as a mechanism for such negative food effect and demonstrate a prodrug approach to mitigate food effect. Effect of food composition on fed state oral bioavailability of LB30870 was studied in dogs. Various prodrugs were synthesized, and their solubility, permeability, and trypsin binding affinity were measured. LB30870 and prodrugs were subject to cocrystallization with trypsin, and the X-ray structures of cocrystals were determined. Food effect was studied in dogs for selected prodrugs. Protein or lipid meal appeared to affect oral bioavailability of LB30870 in dogs more than carbohydrate meal. Blocking both carboxyl and amidine groups of LB30870 resulted in trypsin Ki values orders of magnitude higher than that of LB30870. Prodrugs belonged to either Biopharmaceutical Classification System I, II, or III. X-ray crystallography revealed that prodrugs did not bind to trypsin, but instead their hydrolysis product at the amidine blocking group formed cocrystal with trypsin. A prodrug with significantly less food effect than LB30870 was identified. Binding of prodrugs to food components such as dietary fiber appeared to counteract the positive effect brought with the prodrug approach. Further formulation research is warranted to enhance the oral bioavailability of prodrugs. In conclusion, this study is the first to demonstrate that the negative food effect of LB30870 can be attributed to trypsin binding. Trypsin binding study is proposed as a screening tool during lead optimization to minimize food effect.
authors.affiliation: College of Pharmacy, CHA University , 521 CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Lee
authors.affiliation: LG Life Sciences, R&D Center ,188, Munji-ro, Yuseong-gu, Daejeon 34122, Korea.
authors.forename: Bongchan
authors.initials: B
authors.lastname: Kim
authors.affiliation: LG Life Sciences, R&D Center ,188, Munji-ro, Yuseong-gu, Daejeon 34122, Korea.
authors.forename: Tae Hun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: LG Life Sciences, R&D Center ,188, Munji-ro, Yuseong-gu, Daejeon 34122, Korea.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Lee
authors.affiliation: LG Life Sciences, R&D Center ,188, Munji-ro, Yuseong-gu, Daejeon 34122, Korea.
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Park
authors.affiliation: LG Life Sciences, R&D Center ,188, Munji-ro, Yuseong-gu, Daejeon 34122, Korea.
authors.forename: Kyungha
authors.initials: K
authors.lastname: Chung
authors.affiliation: LG Life Sciences, R&D Center ,188, Munji-ro, Yuseong-gu, Daejeon 34122, Korea.
authors.forename: Sung-Hack
authors.initials: SH
authors.lastname: Lee
authors.affiliation: LG Life Sciences, R&D Center ,188, Munji-ro, Yuseong-gu, Daejeon 34122, Korea.
authors.forename: Seungyup
authors.initials: S
authors.lastname: Paek
authors.affiliation: Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 02792, Korea.
authors.forename: Eunice EunKyeong
authors.initials: EE
authors.lastname: Kim
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation , 41061 Daegu, Korea.
authors.forename: SukKyoon
authors.initials: S
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, CHA University , 521 CHA Bio Complex, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Korea.
authors.forename: Aeri
authors.initials: A
authors.lastname: Kim
mesh_terms: D000578:Amidines / Q000737:chemistry; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D000991:Antithrombins / Q000737:chemistry*; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry; D004285:Dogs; D004355:Drug Stability; D005463:Fluoroacetates; D006801:Humans; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000578:Amidines; D000925:Anticoagulants; D000991:Antithrombins; D004151:Dipeptides; D005463:Fluoroacetates; C476981:N-aminosulfonyldiphenylalanyl-prolyl-((4-amidinophenyl)methyl)amide; D011355:Prodrugs; D013917:Thrombin
keywords: anticoagulant; cocrystal; dietary fiber; food effect screening; trypsin