Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA)

Abstract

In knee OA patients, microsphere-based TA delivery via a single IA injection prolonged SF joint residency, diminished peak plasma levels, and thus reduced systemic TA exposure relative to TAcs.

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

“…Extension of tissue trauma‐induced instability may have incited the effects of extended exposure found here. Although the differences in joint subluxation as change finding could not be statistically substantiated and would require additional studies with larger sample sizes to be proven, a role of extension of instability was supported by inhibition of cell outgrowth from tissue explants in culture: To address the possible mechanisms responsible for the effects of extended exposure to TAA, we studied its effect on wound healing in vitro, using a TAA concentration based on the range expected to be present in the synovial fluid (Hunder & Gleich, ; Kraus et al, ; Wallis et al, ). The continuous presence of TAA resulted in a complete block of migration of ligament or synovial capsule cells out of tissue explants in culture.…”

“…Hence, the extended exposure to TAA in the current study may have inhibited the general and naturally occurring arthrofibrosis in OA, a normal process leading to stabilization and stiffness of the joint (Shelbourne, Patel, & Martini, ). It has to be noted that the in vitro models used may have been suboptimal in reflecting the dynamic changes in synovial fluid concentrations over time, as only one dosage was used at a concentration well over the anticipated receptor saturation concentration (Mayer, Kaiser, Milholland, & Rosen, ), and exposure was limited to 10 days, whereas TAA released from MSs in vivo was detected up until 12 weeks after IA injection (Kraus et al, ). However, this is more likely to have caused an underestimation rather than overestimation of the effects found in vivo.…”

“…PEA MSs loaded with a hydrophobic near IR dye were shown to still contain dye up until 70 days after injection in a rat OA model (Rudnik‐Jansen et al, ), suggesting that release continued until at least the first 10 weeks. Moreover, in knee OA patients treated with a PLGA‐based platform releasing TAA (Kraus et al, ), TAA was detected in the synovial fluid of knee OA patients up to 12 weeks after IA injection, but not in bolus injected joints. As we have shown in an acute arthritis model that PEA MS‐based TAA release inhibited inflammation for a longer time period than PLGA‐based TAA release (Rudnik‐Jansen, Woike, et al, ), it is very likely that in the current study, release spanned even more than these 12 weeks.…”

“…Subsequently, wells were washed and replenished with fresh medium containing 10 −6 ‐M (=1 μM) TAA or ethanol control. The concentration was chosen based on previously shown relationships of synovial fluid–serum concentration ratios (Hunder & Gleich, ; Wallis, Simkin, & Nelp, ), with plasma level of 2 μM corresponding to synovial fluid concentrations of approximately 4 μM or higher, and on a study showing that injection with PLGA MSs loaded with half the amount of TAA used here in human OA joints, that resulted in a concentration of 0.7 μM in aspirated synovial fluid after 1 week (Kraus et al, ). Images were obtained at time point 0, 24, and 48 hr after scratch.…”

“…Despite the frequent use of IA application in clinical practice, IA use of TAA is contraindicated in the treatment of unstable joints. However, no scientific background or clinical evidence for this contraindication is provided in literature (McAlindon et al, 2017;McCormack, Lamontagne, Vannabouathong, Deakon, & Belzile, 2017), with even some opposing results (de la Harpe & Brighton, 1989;Geborek, Mansson, Wollheim, & Moritz, 1990;Guma et al, 2002;Kraus et al, 2018). This is in contrast to the acute tissue injury occurring in ligament tears leading to instability-induced OA in human patients (Buckwalter & Brown, 2004), which may be affected differently by prolonged exposure to corticosteroids.…”