Pharmacokinetic and biodistribution (PK/BD) study of ProGel-Dex, a thermoresponsive dexamethasone prodrug for sustained joint pain relief in a mouse model of osteoarthritis.

Abstract

Intraarticular (IA) administration of ProGel-Dex was previously found to provide sustained joint pain relief with excellent safety in arthritis animal models. To explore ProGel-Dex' working mechanisms, we conducted a comprehensive pharmacokinetics/biodistribution (PK/BD) study of IA ProGel-Dex and the free Dex released in an osteoarthritis mouse model. An initial "burst" release and distribution of ProGel-Dex was observed in all organs/tissues post IA administration. The higher-than-1.5 AUC/AUCratios for both ProGel-Dex and free Dex support their long-term presence within the DMM joint beyond the experimental endpoint. The overall systemic organ/tissue exposures to ProGel-Dex and free Dex released were found to be much lower than those detected within the OA joint with IA ProGel-Dex. Together, these data support that the potent and long-sustained OA joint pain relief and the excellent safety of IA ProGel-Dex can be attributed to its prolonged retention in OA joint and the pathology-driven local activation.