EFFECTS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN A SLOW-RELEASE HYLAN VEHICLE ON RAT TYPE-II COLLAGEN ARTHRITIS

Purpose. To determine the effect of hylan fluid (HA), a model slow rel ease vehicle on the pharmacokinetic profile and efficacy of interleuki n-1 receptor antagonist (IL-1ra) in rats with established type II coll agen arthritis. Methods. Female Lewis rats with type II collagen arthr itis were treated daily, every other day or every third day with singl e subcutaneous (sc) injections of IL-1ra formulated in HA and the effe cts on arthritis determined. Results were compared to those obtained w ith IL-1ra in citrate buffered saline with EDTA and polysorbate (CSEP) . Sequential blood levels were determined in rats injected sc with IL- 1ra in CSEP or HA. Results. Incorporation into HA led to slower releas e of IL-1ra into the bloodstream and maintained therapeutic blood leve ls of IL-1ra for a longer time compared to the IL-1ra/CSEP formulation . Single daily sc doses of 100 mg/kg IL-1ra in CSEP were ineffective i n type II collagen arthritis. By contrast, once per day dosing of 100 mg/kg IL-1ra in HA provided 78% inhibition of paw swelling. Every othe r day dosing with 100 mg/kg IL-1ra in HA resulted in 62% inhibition. I L-1ra (100 mg/kg in HA) given every third day provided 19% inhibition of arthritis. Improved efficacy correlated with improved pharmacokinet ics. Conclusions. Administration of IL-1ra in the slow release vehicle HA improves pharmacokinetics and efficacy in rat type II collagen art hritis.