Safety and Systemic Exposure of Triamcinolone Acetonide Following Ultrasound-Guided Intra-Articular Injection of Triamcinolone Extended-Release or Standard Triamcinolone Acetonide in Patients with Shoulder Osteoarthritis: An Open-Label, Randomized Study

Abstract

Background and Objectives Osteoarthritis (OA) is a major public health burden. While knee and hip joints are most commonly affected, the glenohumoral (shoulder) joint is also frequently involved. We evaluated the pharmacokinetics and safety/tolerability of triamcinolone acetonide extended-release (TA-ER) and triamcinolone acetonide crystalline suspension (TAcs) in patients with shoulder OA. Methods In this phase 2, randomized, open-label, single-dose study (NCT03382262), adults with moderately-to-severely symptomatic shoulder OA for ≥ 6 months randomly received a single ultrasound-guided intra-articular (IA) injection of TA-ER 32 mg or TAcs 40 mg. Safety was evaluated throughout 12 weeks post-injection; blood samples for pharmacokinetic evaluations were collected pre-injection and through Day 85 post-injection. Results Among 25 randomized patients, 12 received TA-ER and 13 received TAcs. Most patients were female (60%), and all had moderate (72%) or severe (28%) shoulder OA. Adverse events (AEs) were reported by four (33%) patients following TA-ER and three (23%) following TAcs injection. No AE was serious or led to study discontinuation. Systemic exposure following TAcs was approximately 1.5-fold higher than that following TA-ER injection (geometric mean [GM] AUC 0–last 873,543 vs 557,602 h × pg/mL). GM C max was also higher in TAcs- than TA-ER-treated patients (2034 vs 1283 pg/mL). Bioequivalence testing confirmed lower systemic TA exposure following TA-ER than TAcs IA injection. Conclusion These pharmacokinetic data confirm protracted release of TA from TA-ER following IA injection in patients with shoulder OA. Lower peak and systemic TA exposure following TA-ER suggests TA-ER could potentially confer an improved systemic safety profile over TAcs. Trial Registration Number NCT03382262 (December 22, 2017 retrospectively registered).

A Randomized, Open-Label, Single-Dose Study to Assess Safety and Systemic Exposure of Triamcinolone Acetonide Extended-Release in Patients With Hip Osteoarthritis

“…Three occurrences, representing a 20% incidence, of incomplete administration of TA-ER during ultrasound-guided hip injection were observed and were unexpected. Incomplete administration has not been noted in clinical studies involving hundreds of patients receiving TA-ER injections into the knee joint, or in a small study of TA-ER injections into the glenohumeral joint in patients with shoulder OA [ 26 ]. The standard anterior approach to the hip joint in patients in a supine position may have contributed to this observation with injection of the TA-ER microsphere suspension.…”

The Emerging Era of Interventional Imaging in Rheumatology: An Overview During the Coronavirus Disease-2019 (COVID-19) Pandemic

“…US-guided injection of the shoulder proved effective regardless the procedure for injection (anterior, posterior, or lateral) and was effective for post-injection evaluation. 40 US-guided injection of the shoulder via the rotator interval technique is used for arthrograms, and intra-articular shoulder joint injections. 41 US-guided steroid injection procedure provides a dramatic improvement.…”

Optimization and modeling of PEGylated, hydrocortisone‐17‐butryate‐loaded poly(lactic‐co‐glycolic acid) microspheres

“…Thus the patient can remain within the proper therapeutic dosing window for a longer duration post‐injection. [ 7–9 ] Through this mechanism, increased therapeutic efficacy can be achieved via increasing bioavailability while concurrently reducing local and systemic side effects of high‐dose corticosteroid therapies. [ 3,10 ]…”

“…Zilretta, the first FDA approved extended-release formulation for intraarticular corticosteroid injections, has demonstrated dramatic reductions in harmful peak corticosteroid concentrations through the encapsulation of triamcinolone acetonide (TA) while outperforming equivalent bolus injections in patient comfort for the full duration of clinical trials. [7,8] By utilizing PLGA as a polymeric encapsulant, the release of corticosteroid within the synovium can be engineered to provide the same dosage over a longer period. Thus the patient can remain within the proper therapeutic dosing window for a longer duration post-injection.…”

“…Thus the patient can remain within the proper therapeutic dosing window for a longer duration post-injection. [7][8][9] Through this mechanism, increased therapeutic efficacy can be achieved via increasing bioavailability while concurrently reducing local and systemic side effects of high-dose corticosteroid therapies. [3,10] Furthermore, PEGylation, the process by which polyethyleneglycol (PEG) is conjugated onto biologically exposed proteins or complexes, has been proven to reduce systemic filtration and targeted destruction of the payload.…”