A Shah1 , M Woodruff2 , V Agarwal3 , P Liu4 , P Sundaresan5
1Bayer Corporation, West Haven, CT, 2Bayer Corporation, West Haven, CT, 3Bayer Corporation, West Haven, CT, 4Bayer Corporation, West Haven, CT, 5Bayer Corporation, West Haven, CT,
Purpose.
BAY 12-9566 is an inhibitor of matrix metalloproteinase-3 that is being developed for osteoarthritis (OA) and cancer. The purpose of this study was to define the pharmacokinetic (PK) interaction between BAY 12-9566 and common (naproxen, ibuprofen) nonsteroidal anti-inflammatory drugs (NSAIDs) during co-administration in patients with (OA). The safety and tolerability of BAY 12-9566 co-administered with NSAIDs was also assessed. Methods. Ninety male or female patients 45 years and older with a diagnosis of OA for at least 3 months were enrolled in this study. Each NSAID group had 45 patients who were randomized to one of the 3 treatment groups (BAY 12-9566 400 mg, 100 mg or placebo) on a 1:1:1 basis. Steady-state PK for NSAID alone was determined on Day -2. BAY 12-9566 or placebo dosing alone was started on Day 1; blood samples were collected for steady state PK of BAY 12 9566 alone on Day 14. On Day 15, the fixed dose of NSAID was started with the continuation of BAY 12-9566/ placebo dosing. Blood samples were collected for steady state PK of NSAID and BAY 12-9566 during co-administration on Day 28. Dosing with a fixed dose of NSAID and BAY 12-9566 was continued until Day 42. Results. Although there was a decrease in total naproxen concentration and total BAY 12-9566 concentration when co-administered, the free concentrations for both naproxen and BAY 12-9566 remained unchanged. When ibuprofen and BAY 12-9566 were co-administered, there was a decrease in the total ibuprofen concentration, however, free concentration for ibuprofen remained about the same. Total concentrations of BAY 12-9566 were unchanged and the free concentrations were about the same. The most commonly reported events during this period were diarrhea (5 patients), accidental injury (4 patients), headache (3 patients) and dyspepsia (3 patients). With the exception of headache, these events were reported by patients in both NSAID groups and in both the placebo and BAY 12-9566 groups. Headache was reported only in patients receiving ibuprofen (one placebo patient and two patients in the BAY 12-9566 400 mg group). All other events were reported by two or fewer patients overall. Conclusions. BAY 12-9566 at doses of 100 and 400 mg can be safely administered concurrently with naproxen and ibuprofen to patients with OA.