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

Abstract

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.

Effects of SKCPT on Osteoarthritis in Beagle Meniscectomy and Cranial Cruciate Ligament Transection Models

“…OA is a degenerative condition characterized by progressive joint cartilage deterioration, manifesting as pain and stiffness in the joints [32]. Multiple factors, including advanced age, genetic predisposition, obesity, previous joint injuries, and repeated joint use, contribute to the etiology of OA [2,33].…”

Polymer particles for the intra-articular delivery of drugs to treat osteoarthritis

“…A phase 2 clinical trial recently began to evaluate the safety, efficacy, and pharmacokinetics of EP-104AR in patients with knee OA. The system is composed of crystals of the corticosteroid fluticasone propionate, coated with a semipermeable shell of heat-treated PVA, resulting in particles with mean diameters in the range of 50-100 µm [110]. To determine the pharmacokinetic profile of EP-104AR, 0.6 mg and 12 mg doses were injected IA into Beagle dogs.…”

“…On the other hand, the encapsulation of drugs into more hydrophobic polymers like PLGA [76,87], PDLLA [93], and PEAs [97][98][99][100] can lead to the release of drug over months. Nevertheless, even particles that released drug over months in vitro exhibited burst-type release profiles in vivo, with high and then rapidly decreasing concentrations of drug in the joint, suggesting there are additional factors such as enzymes and trafficking of the particles out of the joint that occur in vivo [78,110]. Engineering the release profile of a drug from the delivery system is a complex issue.…”

Recent Advances in Clinical Translation of Intra‐Articular Osteoarthritis Drug Delivery Systems

“…[ 142 ] This formulation was administered IA to beagle dogs (0.6 or 12 mg). [ 143 ] Low‐dose EP‐104IAR did not exhibit detectable levels of FP in the plasma, while high‐dose EP‐104IAR demonstrated plasma concentrations of ≈300 pg mL −1 3 days post‐injection, which declined below detectable levels by day 7. High‐dose EP‐104IAR also maintained detectable synovial fluid levels of FP out to day 60 of the study (geometric mean 142.7 ng mL −1 ), a trend which was also reflected in cartilage levels of FP (geometric mean 53.9 ng mL −1 ).…”