Safety and pharmacokinetics of EP-104IAR (sustained-release fluticasone propionate) in knee osteoarthritis: A randomized, double-blind, placebo-controlled phase 1 trial.

Objective: EP-104IAR is a novel, sustained-release, intra-articular (IA) formulation of the corticosteroid fluticasone propionate (FP), in development for the treatment of osteoarthritis (OA) pain. This study evaluated the safety, pharmacokinetics (PK) and efficacy of a single dose of EP-104IAR in patients with OA of the knee. Design: This was a multi-center, randomized, double-blind, placebo-controlled trial performed at 3 sites in Canada. Subjects with moderate to severe pain received either a single dose of the investigational product EP-104IAR (15 â€‹mg) or placebo (vehicle) and were evaluated for up to 42 weeks. The primary outcome measures were safety and PK. The study was not powered to assess efficacy, however patient reported outcome measures were analyzed to evaluate pain and symptom relief. Results: Thirty-two subjects were randomized (21 women, 11 men, mean age: 64.8 years). EP-104IAR was well tolerated. Average serum cortisol levels showed no clinically significant deviations compared to placebo and remained within the normal range of cortisol variation. Plasma PK concentrations were within acceptable safety margins, compared to marketed FP products. Synovial fluid FP levels were approximately 2 orders of magnitude higher and at efficacious concentrations for most subjects. Efficacy evaluations indicated that EP-104IAR provided an immediate improvement of OA symptoms and these effects persisted for 8-12 weeks consistently across all measures. Conclusions: This study provides evidence that 15 â€‹mg of EP-104IAR is well tolerated and has the potential for efficacy in OA patients. These data support further examination of EP-104IAR in larger clinical studies.

Pharmacokinetic Profile of Intra-articular Fluticasone Propionate Microparticles in Beagle Dog Knees.

OBJECTIVE: The objective of this pilot study was to determine time point(s) at which maximum concentration of fluticasone propionate (Cmax) occurs in synovial fluid and plasma in Beagle dog knees after intra-articular injection of EP-104IAR. DESIGN: EP-104IAR is composed of fluticasone propionate drug crystals coated with heat-treated polyvinyl alcohol (PVA) to result in extended release properties. Thirty-two Beagle dogs had an injection of EP-104IAR into the knee joint at 2 different dose levels (0.6 mg and 12 mg). Outcome measures included plasma, synovial fluid, and articular cartilage fluticasone propionate concentrations as well as histological analysis of cartilage and synovium at a variety of time points up to 58 days postdosing. RESULTS: Intra-articular administration of 0.6 and 12 mg EP-104IAR was well tolerated. Early minor abnormalities found on microscopy resolved by the end of the study. There were no quantifiable concentrations of fluticasone propionate in plasma of animals administered 0.6 mg at any of the sampling time points. Highest concentrations in plasma following 12 mg administration occurred 1 day postdose and declined with a half-life of approximately 45 days. Highest concentrations of fluticasone propionate in synovial fluid and cartilage generally occurred 5 days postdose in both dose groups and declined with a half-life of approximately 11 to 14 days. CONCLUSIONS: EP-104IAR is capable of providing a safe and prolonged local exposure to a corticosteroid in the synovial joint while minimizing systemic exposure, with peak exposures occurring within a matter of days after dosing before declining in all tissues in a predictable manner.