Treatment of the injured joint with rhPRG4 is based on recent observations that inflammation diminishes expression of native PRG4. Re-establishing lubrication between pressurized and sliding cartilage surfaces during locomotion promotes the nascent expression of PRG4 and thus intra-articular (IA) treatment strategies should be supported by pharmacokinetic evidence establishing the residence time of rhPRG4. A total of 21 Yucatan minipigs weighing ∼55 kg each received 4 mg of ¹³¹ I-rhPRG4 delivered by IA injection 5 days following surgical ACL transection. Animals were sequentially euthanized following IA rhPRG4 at 10 min (time zero), 24, 72 h, 6, 13 and 20 days later. The decay of the ¹³¹ I-rhPRG4 was measured relative to a non-injected aliquot and normalized to the weight of cartilage samples, menisci and synovium, and known cartilage volumes from each compartment surface obtained from representative Yucatan minipig knees. Decay of ¹³¹ I-rhPRG4 from joint tissues best fit a two-compartment model with an α half-life (t_1/2α ) of 11.28 h and β half-life (t_1/2β ) of 4.81 days. The tibial and femoral cartilage, meniscii, and synovium retained 7.7% of dose at 24 h. High concentrations of rhPRG4 were found in synovial fluid (SF) that was non-aspiratable and resided on the articular surfaces, removable by irrigation, at 10 min following ¹³¹ I-rhPRG4 injection. Synovial fluid K21 exceeded K12 and SF t_1/2β was 28 days indicating SF is the reservoir for rhPRG4 following IA injection. Clinical Significance: rhPRG4 following IA delivery in a traumatized joint populates articular surfaces for a considerable period and may promote the native expression of PRG4. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:386-396, 2019.

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