Intra-articular injection of an extended-release flavopiridol formulation represents a potential alternative to other intra-articular medications for treating equine joint disease.

ABSTRACT

OBJECTIVE: To establish the pharmacokinetics of the cyclin-dependent kinase-9 inhibitor flavopiridol in equine middle carpal joints, using an extended-release poly lactic-co-glycolic acid (PLGA) microparticle formulation. ANIMALS 4 healthy horses without evidence of forelimb lameness. METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 µg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points. RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point. CLINICAL RELEVANCE Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.