Pharmacokinetics of intraarterial calcineurin inhibitor delivery to composite tissue: A study of regional and systemic advantages of intraarterial delivery of calcineurin inhibitors (cyclosporine and tacrolimus) to a vascularly isolated rabbit forelimb

Currently available treatment modalities have not been able to fully rehabilitate many individuals with composite tissue defects. Safe and effective immunosuppressive therapy is essential before hand and musculoskeletal transplantation can be accepted as a reliable mode of reconstruction. We have evaluated the potential pharmacokinetic benefits of local (intra-arterial) delivery of cyclosporine (CSA) and tacrolimus (FK506) in a vascularly-isolated rabbit forelimb model that simulates conditions of composite tissue allografting CSA or FK506 was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits using clinically relevant doses. On day 6, drug levels were in blood, as well as in skin, muscle, bone, and bone marrow samples from both right (R) left (L) forearms of each rabbit, and mean R:L tissue concentration ratios derived.; Intra-arterial did not reduce systemic exposure, when compared with same dose intravenous treatment. Intra-arterial CSA infusion, at doses greater than 1 mg/kg/d, produced a large (3- to 14-fold) regional advantage in all limb tissues in the presence of low systemic blood levels. In contrast, only a minimal regional advantage of local FK delivery was obtained in all forelimb tissues at the 3 doses studied, despite production of supra-therapeutic blood levels. We conclude that FK506 is pharmacokinetically inferior to CSA for intra-arterial infusion of the rabbit forearm. Our findings suggest low dose intra-arterial infusion of CSA (but not FK506) might be useful in preventing limb transplant rejection while minimizing systemic toxicity.