Optimal dosing of intravenous tacrolimus following pediatric heart transplantation

Background: Early experience with intravenous tacrolimus at high doses (0.1 -0.15 mg/kg/day) was associated with frequent clinical toxicity. The optima l dosing regimen after pediatric heart transplantation is unknown. Methods: We retrospectively reviewed data on the last 45 pediatric heart tr ansplant recipients to document the time required to achieve therapeutic bl ood levels and the safety of 2 differing intravenous dosing regimens (tacro limus 0.03 & 0.05 mg/kg/day as continuous IV infusion). Target plasma level s were (1.2-1.7 ng/ml) with levels >2.0 ng/ml considered toxic, and target whole blood levels were 15-20 ng/ml with levels >25 ng/ml considered toxic. Results: Mean age at transplantation was 7.5 +/- 5.6 years (0.1-18), and 14 were infants. Intravenous tacrolimus was commenced at a mean of 7 +/- 3 ho urs (range 2-16) after arrival in the ICU. Eight patients were excluded fro m analysis because of protocol modifications. Of the remaining 37 pts, 9 re ceived initial infusion at 0.03 mg/kg/day; 3 (33%) achieved 'therapeutic' l evels within 48 hours and 1 patient had a toxic level (27 ng/ml) at 36 hour s. Twenty-eight patients received 0.05 mg/kg/day; 18 (64%) achieved therape utic levels within 48 hours and 9 (32%) developed toxic levels. Patients wi th toxic whole blood levels had higher tacrolimus levels on first blood ass ay compared to those who did not develop toxicity (16.4 +/- 3.4 vs 9.3 +/- 3.9, p < .0001; level >10 ng/ml on first assay in 7/7 toxic patients vs 7/1 9 without toxicity, p = .004). Patients receiving the higher dose regimen h ad fewer episodes of moderate or severe rejection (greater than or equal to Grade 3A) at first biopsy than those receiving the lower dose infusion (32 % vs 75%; p = .046). No patient required renal dialysis. Conclusions: Dosing below 0.05 mg/kg/day may result in clinically important delay in achieving therapeutic levels. Toxicity may be reduced by frequent monitoring of levels for the first 48 hours after transplantation especial ly when the initial Level is >10 ng/ml.