Safety, pharmacokinetics (PK), and pharmacodynamics (PD) of WAY-195725

Abstract

Background WAY-195725 can selectively and reversibly inhibit cytosolic phospholipase A2α (cPLA2α) to block the biosynthesis of prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and platelet-activating factor by inhibiting the release of arachidonic acid. It has been proposed treatment for the management of rheumatoid arthritis, osteoarthritis, and dysmenorrhea. Objective To evaluate the safety, PK, and PD of WAY-195725 following oral single dose administration in healthy subjects. Methods Healthy subjects (N=90) were studied in a randomized, double-blind, placebo-controlled, positive (ibuprofen)-controlled, ascending single dose study. The safety, tolerability, PK, and PD of WAY-195725 (10–600 mg) were assessed. A23187 (Ca++ ionophore) was used to stimulate whole blood ex vivo to produce PGE2, LTB4, and TXB2. Results The oral absorption of WAY-19725 was slow (tmax: 2~3 h). WAY-195725 inhibited PGE2, TXB2 and LTB4 with mean IC50 (ng/mL) of 40.2, 40.8 and 199, respectively. Ibuprofen, a positive control, inhibited both PGE2 and TXB2, but not LTB4, which coincides to ibuprofen's pharmacological profile as a COX-1,2 inhibitor. WAY-195725 was well tolerated in all the dose cohorts. Conclusion Significant WAY-195725 concentration-dependent inhibition is apparent for all three biomarkers (PGE2, TXB2 and LTB4), which conforms to WAY-195725's pharmacological profile as a potent cPLA2α inhibitor. Clinical Pharmacology & Therapeutics (2005) 77, P51–P51; doi: 10.1016/j.clpt.2004.12.086