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

OBJECTIVE

Osteoarthritis (OA) is a prevalent and debilitating degenerative joint disease in both humans and companion animals, leading to chronic pain and mobility loss. The inflammation has been identified to play a critical role in OA progression. Our prior work revealed that cyclin-dependent kinase 9 acts as a key regulator of early inflammatory gene activation and found an effective inhibitor, flavopiridol. To develop flavopiridol into an effective prevention and treatment of OA, this study focuses on the pharmacokinetics of our flavopiridol formulations upon IA injection.

METHODS

12 male 14-week-old Lewis rats (n = 4 per group) received IA administration of flavopiridol in either free form or encapsulated in poly(lactic-co-glycolic acid) microparticles. Blood samples were collected via the saphenous vein at multiple time points. Plasma flavopiridol concentrations were quantified using a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were determined by noncompartmental analysis.

RESULTS

Free flavopiridol exhibited a higher peak plasma concentration and a shorter elimination half-life than that of poly(lactic-co-glycolic acid) microparticle encapsulated formulations. In contrast, microparticle formulation provided sustained release of flavopiridol for at least 3 weeks, with a significantly lower mean peak plasma concentration and prolonged elimination half-life.

CONCLUSIONS

Free flavopiridol has a short elimination half-life and limited systemic retention. In contrast, IA administration of microparticle encapsulated inhibitors offers sustained release and prolonged drug exposure at the target site while minimizing systemic side effects.

CLINICAL RELEVANCE: The microparticle-based sustained-release formulation provides a promising means for the prevention and long-term treatment of joint inflammation and OA in both humans and animals.