Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA.
Department of Orthopedic Surgery, School of Medicine, University of California-Davis, Davis, CA.
Am J Vet Res. 2024 Jun 21;85(9). doi: 10.2460/ajvr.24.03.0057. Print 2024 Sep 1.
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.
4 healthy horses without evidence of forelimb lameness.
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.
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.
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.
建立环磷腺苷依赖性激酶-9 抑制剂 flavopiridol 在马腕中关节的药代动力学，使用延长释放聚乳酸-羟基乙酸共聚物（PLGA）微球制剂。
4 匹无前肢跛行证据的健康马。
在 4 匹健康马中进行了 6 周的纵向药代动力学研究，分为 2 个阶段（各 6 周）。3 mL 生理盐水中含有 122μg flavopiridol 的 PLGA 微球通过关节内注射到 1 个腕中关节，对侧关节注射空 PLGA 微球作为对照。在 6 周的时间点采集关节滑液和血浆，并使用验证的方案测定关节滑液和血浆中的药物浓度。在每个时间点都进行了关节滑液总蛋白和总核细胞计数和分类、全血细胞计数、血清生化和跛行检查。
第 1 周时关节滑液中的 flavopiridol 平均为 19 nM，逐渐减少到第 4 周的 1.4 nM，第 5 和第 6 周时通常低于检测限。在血浆样本中未检测到 flavopiridol，在任何时间点均未观察到不良反应。
PLGA 微球包封 flavopiridol 的关节内注射在马中耐受性良好，在 4 周内关节滑液中可检测到 flavopiridol，而系统暴露可忽略不计。Flavopiridol 是一种环磷腺苷依赖性激酶-9 抑制剂，具有强大的抗炎和镇痛作用。延长释放微球制剂促进了药物在关节内的保留，它可能是治疗马关节疾病的其他关节内药物的替代药物。
