The Therapeutic Efficacy of Local Delivery of a Combination of Tacrolimus and Mycophenolic Acid Along With Lower Doses of Systemic Immunotherapy in Prolongation of The Composite Tissue Allograft Survival With a Minimum Systemic Toxicity.

Abstract

Listen

Translate article

Wide spread use of vascularized composite tissue allo-transplantation (VCA) is limited by the side effects of the life-long systemic immunosuppression. Alternative therapies to avoid both the acute rejection and the complications of the life-long systemic immunosuppression are needed. VCA provides a unique opportunity for the local delivery of the drugs directly to the graft. Therefore, the goal of our study is to investigate the therapeutic efficacy of the local delivery of a combination of tacrolimus and mycophenolic acid along with lower doses of systemic immunotherapy in the prolongation of the survival of the composite tissue allograft with a minimum systemic toxicity. Brown Norway -to- Lewis rat orthotopic hind limb transplants were performed and received 0.1mg/kg/day of tacrolimus intraperitoneally. Topical application of no treatment (Control), tacrolimus 0.1% ointment, mycophenolic acid 1% lipoderm, and a combination of the two topical formulations were initiated at day 0 to overlap with the systemic therapy. Treatment was continued until grade III rejection. Tail vein sampling was performed at days 4, 7, 14, and at sacrifice. Whole blood trough levels of tacrolimus, and plasma trough concentrations of mycophenolic acid was analyzed by HPLC-MS, and HPLC. Tissue biopsies (Skin, muscle, and lymphatic nodes) were collected at end point for tissue drug levels, as well as for storage in formalin and OCT for histopathology and IHC. Systemic toxicity was evaluated using 24hr urinary creatinine excretion. Best outcomes were obtained in group (n=6) treated with a combination of the two topical formulations in a conjunction with low dose of systemic immunotherapy (Allograft Survival > 100 days). Drugs levels were low or undetectable in blood and/or plasma, whereas tissue levels were significantly higher than blood levels (P<0.05). 24 hr urinary creatinine excretion were in the normal range. Histological evaluation was correlated with the clinical sign of rejection. We concluded that local delivery of a combination of tacrolimus, and mycophenolic acid along with lower doses of systemic immunotherapy was successful in prolongation of the composite tissue allograft survival with a minimum systemic toxicity.