1 research outputs found
A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It
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 <i>K</i><sub>i</sub> 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