Sustained efficacy of a single intra-articular dose of FX006 in a rat model of repeated localized knee arthritis

被引:61
作者
Kumar, A. [1 ]
Bendele, A. M. [2 ]
Blanks, R. C. [3 ]
Bodick, N. [1 ]
机构
[1] Flexion Therapeut Inc, Burlington, MA USA
[2] Bolder BioPATH Inc, Boulder, CO USA
[3] Ardelyx, Fremont, CA USA
关键词
Corticosteroids; Intra-articular; Sustained-release; Animal model; Synovitis; Joint protection; SYNOVIAL-MEMBRANE INFLAMMATION; WALL-INDUCED ARTHRITIS; ARTICULAR-CARTILAGE; EXPERIMENTAL OSTEOARTHRITIS; TRIAMCINOLONE ACETONIDE; METHYLPREDNISOLONE ACETATE; RHEUMATOID-ARTHRITIS; OSTEOPHYTE FORMATION; DOUBLE-BLIND; INTERLEUKIN-1;
D O I
10.1016/j.joca.2014.09.019
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
Objective: To evaluate the efficacy of a single intra-articular (IA) dose of FX006, an extended-release formulation of triamcinolone acetonide (TCA) in poly(lactic-co-glycolic acid) (PLGA) microspheres, on the sequelae of repeated episodes of synovitis. Design: Three flares of localized synovitis in the right knee of rats were induced over 4 weeks following a single IA injection of various doses of FX006, Kenalog (R) (TCA immediate release or TCA IR), or vehicle. Gait scores were employed to assess analgesic effect, and the joints were evaluated by histology at the end of the study. TCA plasma concentrations and corticosterone levels were monitored through the study. Results: A single IA dose of 0.28 mg FX006 significantly improved gait scores through all three reactivations. TCA IR at 0.06 mg (providing comparable plasma TCA exposure, 10-fold higher C-max) demonstrated comparable benefit through the first reactivation only and reduced-to-no efficacy thereafter. Significantly improved histological joint scores were observed with effective doses of FX006 but not with TCA IR. Corticosterone levels were initially decreased following both TCA IR and FX006 treatment, but recovered by Day 14. Conclusions: In localized, repeated synovitis in rats, sustained release of TCA following a single IA injection of FX006 significantly prolonged analgesia relative to TCA IR and significantly improved histological scores with no adverse effect on the HPA axis. Since synovitis can contribute to the pathophysiology of multiple joint diseases such as osteoarthritis (OA), RA and gout, FX006 may be an important treatment option for these conditions. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:151 / 160
页数:10
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