Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs
Abstract Introduction Single intra-articular (IA) injections of poly(lactic-co-glycolic acid) (PLGA) microsphere-based triamcinolone acetonide extended-release (TA–ER; formerly FX006) demonstrated sustained, clinically relevant benefits in patients with knee osteoarthritis. The local effects of TA–E...
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doaj-978adfc99c6e4324aa1882602b9e826a2020-11-24T22:12:33ZengAdis, Springer HealthcareRheumatology and Therapy2198-65762198-65842018-09-015247549810.1007/s40744-018-0125-3Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in DogsNeil Bodick0Toni Williamson1Vibeke Strand2Becca Senter3Scott Kelley4Rogely Boyce5Ruth Lightfoot-Dunn6Flexion Therapeutics, Inc.Flexion Therapeutics, Inc.Division of Immunology/Rheumatology, Stanford University School of MedicineFlexion Therapeutics, Inc.Flexion Therapeutics, Inc.Beechy Ridge ToxPath LLCCrucial Consulting, Inc.Abstract Introduction Single intra-articular (IA) injections of poly(lactic-co-glycolic acid) (PLGA) microsphere-based triamcinolone acetonide extended-release (TA–ER; formerly FX006) demonstrated sustained, clinically relevant benefits in patients with knee osteoarthritis. The local effects of TA–ER were assessed in normal canine knees in three nonclinical studies. Methods Knees were evaluated for up to 6 weeks or 9 months after a single injection of TA–ER (2.1/6.25/18.75 mg TA), or TA crystalline suspension (TAcs, 18.75 mg TA), and for up to 6 months after three injections (every 1 or 3 months) of TA–ER (6.25/18.75 mg TA) or TAcs (18.75 mg). Vehicle-diluent, blank microspheres, and untreated knees were used as controls. Plasma and synovial fluid (SF) TA concentrations and standard histopathological assessment of the synovium were conducted. Articular cartilage morphology was assessed via modified Mankin scoring. Results Plasma and SF concentrations indicated prolonged dose-dependent TA joint residency with TA–ER compared with TAcs. Effects in articular cartilage were dose- and time-dependent and consistent with known effects of corticosteroids in the normal knee. Loss of Safranin O staining occurred, indicative of a reduction in cartilage matrix proteoglycan, and recovered in a similar manner for TA–ER and TAcs across all studies. Structural lesions were infrequent and generally comparable in severity between TA–ER and TAcs but slightly higher in incidence for TA–ER. Focal/multifocal foreign-body responses (FBR) to PLGA were observed in the superficial layer of the synovium, peaking after 4–6 weeks, with significant recovery or complete resolution by month 6. Conclusions These findings suggest that the effects of IA injections of TA–ER on cartilage are predominantly transient, and comparable to those observed with TAcs in the normal canine knee joint. These mild effects in the normal joint differ from the beneficial effects observed with TA–ER and other corticosteroids in disease models. The synovial FBR to PLGA microspheres was focal and transient. Funding Flexion Therapeutics, Inc. Plain Language Summary Plain language summary available for this article.http://link.springer.com/article/10.1007/s40744-018-0125-3Biodegradable polymer drug carrierCartilageCorticosteroidIntra-articularMicrosphereTriamcinolone acetonide extended-release |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Neil Bodick Toni Williamson Vibeke Strand Becca Senter Scott Kelley Rogely Boyce Ruth Lightfoot-Dunn |
spellingShingle |
Neil Bodick Toni Williamson Vibeke Strand Becca Senter Scott Kelley Rogely Boyce Ruth Lightfoot-Dunn Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs Rheumatology and Therapy Biodegradable polymer drug carrier Cartilage Corticosteroid Intra-articular Microsphere Triamcinolone acetonide extended-release |
author_facet |
Neil Bodick Toni Williamson Vibeke Strand Becca Senter Scott Kelley Rogely Boyce Ruth Lightfoot-Dunn |
author_sort |
Neil Bodick |
title |
Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs |
title_short |
Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs |
title_full |
Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs |
title_fullStr |
Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs |
title_full_unstemmed |
Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs |
title_sort |
local effects following single and repeat intra-articular injections of triamcinolone acetonide extended-release: results from three nonclinical toxicity studies in dogs |
publisher |
Adis, Springer Healthcare |
series |
Rheumatology and Therapy |
issn |
2198-6576 2198-6584 |
publishDate |
2018-09-01 |
description |
Abstract Introduction Single intra-articular (IA) injections of poly(lactic-co-glycolic acid) (PLGA) microsphere-based triamcinolone acetonide extended-release (TA–ER; formerly FX006) demonstrated sustained, clinically relevant benefits in patients with knee osteoarthritis. The local effects of TA–ER were assessed in normal canine knees in three nonclinical studies. Methods Knees were evaluated for up to 6 weeks or 9 months after a single injection of TA–ER (2.1/6.25/18.75 mg TA), or TA crystalline suspension (TAcs, 18.75 mg TA), and for up to 6 months after three injections (every 1 or 3 months) of TA–ER (6.25/18.75 mg TA) or TAcs (18.75 mg). Vehicle-diluent, blank microspheres, and untreated knees were used as controls. Plasma and synovial fluid (SF) TA concentrations and standard histopathological assessment of the synovium were conducted. Articular cartilage morphology was assessed via modified Mankin scoring. Results Plasma and SF concentrations indicated prolonged dose-dependent TA joint residency with TA–ER compared with TAcs. Effects in articular cartilage were dose- and time-dependent and consistent with known effects of corticosteroids in the normal knee. Loss of Safranin O staining occurred, indicative of a reduction in cartilage matrix proteoglycan, and recovered in a similar manner for TA–ER and TAcs across all studies. Structural lesions were infrequent and generally comparable in severity between TA–ER and TAcs but slightly higher in incidence for TA–ER. Focal/multifocal foreign-body responses (FBR) to PLGA were observed in the superficial layer of the synovium, peaking after 4–6 weeks, with significant recovery or complete resolution by month 6. Conclusions These findings suggest that the effects of IA injections of TA–ER on cartilage are predominantly transient, and comparable to those observed with TAcs in the normal canine knee joint. These mild effects in the normal joint differ from the beneficial effects observed with TA–ER and other corticosteroids in disease models. The synovial FBR to PLGA microspheres was focal and transient. Funding Flexion Therapeutics, Inc. Plain Language Summary Plain language summary available for this article. |
topic |
Biodegradable polymer drug carrier Cartilage Corticosteroid Intra-articular Microsphere Triamcinolone acetonide extended-release |
url |
http://link.springer.com/article/10.1007/s40744-018-0125-3 |
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