We report on the efficacy and safety of FK506 (tacrolimus) compared with a cyclosporine (CsA)-based immunosuppressive regimen after 1 year of treatment in pediatric liver allograft recipients (< 12 years) participating in a multicenter U.S. randomized trial. Patients received either FK506 or CsA as primary immunosuppression following a first ABO-compatible liver transplant. Intravenous FK506 was initiated at 0.1 mg/kg per day, followed by oral FK506 beginning at 0.3 mg/kg per day. The dose was adjusted to maintain plasma trough levels of 0.5-2.0 ng/ml. The CsA group was treated according to each center's usual protocol. Both groups received the same initial doses of corticosteroids. All rejection episodes were biopsy-proven and a standardized algorithm was adopted for the treatment of rejection. Thirty patients were randomized to the FK506 group and 20 to the CsA group. After twelve months of follow-up 20 patients remained in the FK506 group and 13 in the CsA group. Patient survivals were 80% and graft survival 70% in the FK506 group compared with 81% and 71% respectively, in the CsA group. 48% of the FK506 group remained rejection-free compared with 21% of the CsA group, and 79% of FK506-treated patients did not require OKT3 compared with 68% of CsA treated patients. The cumulative corticosteroid dose was less at each time point throughout the first year in the FK506 group. The incidence of serious and minor infections was similar in both groups. Nephrotoxicity, neurotoxicity, and gastrointestinal disturbances were the major toxicities reported. Differences did not reach statistical significance between the two groups although major neurologic events, diarrhea and dyspepsia were more often reported in the FK506 group. There was no difference in mean serum creatinine at 12 months between the two groups. There was a tendency toward lower mean serum cholesterol in the FK506 group. There was no hirsuitism in the FK506 group compared with a 30% incidence in the CsA group. In conclusion, compared with CsA, there is a trend toward less rejection in FK506-treated pediatric allograft recipients, while both drugs have a similar spectrum of side effects.

Background. Tacrolimus (FK 506), a macrolide compound isolated from a bacterium, is a potent immunosuppressant with activity in solid-organ transplants. Most immunosuppressive regimens for liver transplantation are based on cyclosporine.Methods. We conducted an open-label, randomized, multicenter trial to compare the efficacy and safety of tacrolimus-based and cyclosporine-based immunosuppressive regimens for patients receiving a first liver transplant. A total of 478 adults and 51 children (less than or equal to 12 years of age) were randomly assigned at the time of transplantation to receive tacrolimus (n = 263) or cyclosporine (n = 266) and were followed for one year. The primary end points were patient and graft survival at one year. The secondary end points were the incidence of acute rejection, corticosteroid-resistant rejection, and refractory rejection (continued rejection after two courses of corticosteroids and an intervening course of muromonab-CD3).Results. According to Kaplan-Meier analysis, actuarial patient-survival rates at day 360 were 88 percent for both the tacrolimus and cyclosporine groups (P = 0.85; 95 percent confidence interval for the difference, -5.4 to 6.6 percent), and graft-survival rates were 82 percent and 79 percent, respectively (P = 0.55; 95 percent confidence interval for the difference, -4.8 to 9.7 percent). Acute rejection occurred in 154 patients in the tacrolimus group and 173 patients in the cyclosporine group (P<0.002), corticosteroid-resistant rejection occurred in 43 and 82 patients, respectively (P<0.001), and refractory rejection occurred in 6 and 32 patients, respectively (P<0.001). Tacrolimus was associated with a higher incidence of adverse events requiring withdrawal from the study, primarily nephrotoxicity and neurotoxicity; 37 patients in the tacrolimus group and 13 in the cyclosporine group discontinued the study because of adverse events (P<0.001).Conclusions. After one year, immunosuppressive regimens based on tacrolimus and cyclosporine were comparable in terms of patient and graft survival. Tacrolimus was associated with significantly fewer episodes of acute, corticosteroid-resistant, or refractory rejection, but substantially more adverse events requiring discontinuation of the drug.