A randomized, phase IIa study to assess the systemic exposure of triamcinolone acetonide following injection of extended-release triamcinolone acetonide or traditional triamcinolone acetonide into both knees of patients with bilateral knee osteoarthritis

Abstract

Background: Intra-articular corticosteroids are commonly used for pain relief in patients with knee osteoarthritis. Simultaneous intra-articular corticosteroid (CS) knee injections may be beneficial for the ~80-90% of patients who present with, or develop, bilateral knee osteoarthritis, but concurrent injections may increase systemic CS exposure and data on safety/tolerability are lacking. Triamcinolone acetonide extended release (TA-ER) has shown decreased systemic triamcinolone acetonide exposure compared with traditional triamcinolone acetonide crystalline suspension (TAcs) after a single knee injection in patients with knee osteoarthritis. This phase IIa study was designed to assess the safety and systemic triamcinolone acetonide exposure following injections of TA-ER or TAcs into each knee of patients with bilateral knee osteoarthritis.

Methods: Patients (⩾40 years) meeting American College of Rheumatology criteria for knee osteoarthritis in both knees received concurrent single intra-articular injections of TA-ER 32 mg or TAcs 40 mg into each knee (total: 64 mg and 80 mg, respectively) and were followed for 6 weeks. Safety was evaluated based on treatment-emergent adverse events (TEAEs). Blood samples for pharmacokinetic analysis were collected pre-injection, and at the following postinjection time points: 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h, and days 8, 15, 29, and 43.

Results: Baseline characteristics were balanced between patients randomly assigned to TA-ER (n = 12) or TAcs (n = 12). Both treatments were well tolerated with comparable TEAE profiles. Peak plasma triamcinolone acetonide concentrations (Cmax) were lower following bilateral TA-ER injections [geometric mean, 2277.7 pg/ml (95% CI, 1602.13-3238.04)] compared with bilateral TAcs injections [7394.7 pg/ml (2201.06-24,843.43)], with median times to Cmax (Tmax) of 4.5 and 6.5 h, respectively.

Conclusions: In patients with bilateral knee osteoarthritis, intra-articular injection of TA-ER into both knees was well tolerated. Consistent with pharmacokinetic profiles observed after a single knee injection, plasma triamcinolone acetonide concentrations were lower after bilateral TA-ER injections compared with the higher and more variable concentrations observed after bilateral TAcs injections.

Clinicaltrialsgov identifier: NCT03378076.

Keywords: bilateral; corticosteroid; intra-articular; knee; osteoarthritis; pharmacokinetics; safety; triamcinolone acetonide.

Conflict of interest statement

Conflict of interest statement: AK has served on a speaker’s bureau for Flexion Therapeutics, Inc. LK has received research grants from Flexion Therapeutics, Inc. AC and SK are employees of Flexion Therapeutics, Inc. and own stock/stock options in Flexion Therapeutics, Inc. TS declares no conflicts of interest. JL is a former employee of Flexion Therapeutics, Inc. and owns stock/stock options in Flexion Therapeutics, Inc.

© The Author(s), 2019.

Figures

Figure 1.

Study design. aEach patient was evaluated for a total of 6 weeks following bilateral injections. bSafety population: All patients who received study treatment; pharmacokinetic population, all patients from safety population who received both intra-articular injections (one to each knee), completed scheduled sampling, and had sufficient plasma concentration data to allow for calculation of pharmacokinetic parameters. IA, intra-articular; TAcs, triamcinolone acetonide crystalline suspension; TA-ER, triamcinolone acetonide extended-release.

Figure 2.

Plasma triamcinolone acetonide concentrations over time after bilateral injection of TA-ER or TAcs. (a) Log-linear geometric mean (95% CI) baseline to day 43. (b) Linear-linear geometric mean (95% CI) baseline to day 43. (c) Log-linear geometric mean (95% CI) baseline to 24 h. (d) Linear-linear geometric mean (95% CI) baseline to 24 h. CI, confidence interval; TA, triamcinolone acetonide; TAcs, triamcinolone acetonide crystalline suspension; TA-ER, triamcinolone acetonide extended-release.