Pharmacokinetics of intra-articular delivery of flavopiridol-loaded microparticles reveal sustained effects in Lewis rats.

PLGA microparticle-encapsulated flavopiridol provides sustained intra-articular drug release for at least three weeks, minimizing systemic side effects.

This pharmacokinetic study investigated intra-articular (IA) delivery of flavopiridol, a cyclin-dependent kinase 9 (CDK9) inhibitor, in two formulations for the prevention and treatment of osteoarthritis (OA). Twelve male Lewis rats (14 weeks old) were divided into three groups (n=4) receiving IA injections of either free flavopiridol or flavopiridol encapsulated in poly(lactic-co-glycolic acid) (PLGA) microparticles. Plasma drug concentrations were measured via saphenous vein blood sampling at multiple timepoints and quantified using validated liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analysis revealed that free flavopiridol produced a higher peak plasma concentration (Cmax) but a shorter elimination half-life, indicating rapid systemic clearance and limited local retention. By contrast, the PLGA microparticle formulation demonstrated sustained drug release over at least three weeks, with a significantly lower Cmax and markedly prolonged elimination half-life. This sustained-release profile is clinically advantageous as it maintains therapeutic drug concentrations at the target joint while minimizing systemic exposure and associated side effects. OA is a common and debilitating condition in companion animals, and current treatments are largely palliative. Targeting CDK9-mediated inflammatory gene regulation with a sustained-release IA formulation represents a novel mechanistic approach. The PLGA microparticle platform shows strong translational potential for both veterinary and human medicine, offering a promising strategy for long-term management of joint inflammation and OA progression with infrequent dosing requirements.

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