Direct relationship between inhibition of leukotriene release in lung and free plasma concentration of a LTC4synthase inhibitor in a rat model

Cysteinyl leukotrienes (cysLTs; LTC 4 , D 4 , E 4 ), are potent biological lipid mediators playing a central pathophysiological role in asthma. Biosynthesis of cysLTs can be induced by the calcium ionophore, A23187. Inhibition of CysLT release in BAL fluid may be used as a target engagement biomarker of a LTC 4 synthase (LTC4s) inhibitor. It is important to characterize the pharmacocinetic-pharmacodynamic (PKPD) relationship of bimoarkers. The aim of this study was to investigate the relationship between plasma concentration and inhibition of CysLT release in lung after single and repeated oral dosing of a LTC4s inhibitor. Sprague Dawley rats were dosed orally with single or multiple doses of a LTC4s inhibitor. Lung lavage with A23187 and blood sampling for determination of the LTC4s inhibitor plasma concentration was performed at different times after dose. Efficacy was measured as % inhibition of CysLTs in BAL fluid compared to controls. Orally administered LTC 4 s inhibitor effectively inhibited CysLT release in BAL fluid in rat following stimulation with calcium ionophore, with a free plasma concentration for 50% effect (EC 50 ) in the same range as in vitro concentration for 50% inhibition (IC 50 ) in human PBMC. The in vivo PKPD relationship was similar irrespective of time after dosing or duration of treatment, suggesting a direct relationship between plasma concentration and inhibition of CysLTs in lung. Our findings support a new opportunity for LTC 4 s inhibition as a therapeutic target for oral treatment of leukotriene-driven asthma. The specific LTC4s inhibitor investigated in our model shows promising properties for clinical use.