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Safety, pharmacokinetics (PK), and pharmacodynamics (PD) of WAY‐195725
Author(s) -
Zhou H.,
Diehl A.,
Waldman S.,
Shen M.,
Clark J.,
Raible D.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.086
Subject(s) - pharmacology , ibuprofen , pharmacokinetics , pharmacodynamics , tolerability , medicine , chemistry , arachidonic acid , rheumatoid arthritis , adverse effect , biochemistry , enzyme
Background WAY‐195725 can selectively and reversibly inhibit cytosolic phospholipase A 2 α (cPLA 2 α) 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 PGE 2 , LTB 4 , and TXB 2 . Results The oral absorption of WAY‐19725 was slow (t max : 2~3 h). WAY‐195725 inhibited PGE 2 , TXB 2 and LTB 4 with mean IC 50 (ng/mL) of 40.2, 40.8 and 199, respectively. Ibuprofen, a positive control, inhibited both PGE 2 and TXB 2 , but not LTB 4 , 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 (PGE 2 , TXB 2 and LTB 4 ), which conforms to WAY‐195725's pharmacological profile as a potent cPLA 2 α inhibitor. Clinical Pharmacology & Therapeutics (2005) 77 , P51–P51; doi: 10.1016/j.clpt.2004.12.086