Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation

The pharmacokinetics of tacrolimus have been studied in healthy volunteers and in adults undergoing bone marrow transplantation. However, there is little information on the pharmacokinetics of tacrolimus in children undergoing BMT. We studied pharmacokinetics of tacrolimus in seven patients (age 8-17 years) undergoing allogeneic stem cell transplantation. Four patients received matched unrelated donor (MUD) transplants, two underwent HLA-matched related donor transplants, and one underwent an umbilical cord blood donor transplant. All patients received tacrolimus by continuous infusion at 0.03-0.04 mg/kg/day beginning on the day prior to transplant. Tacrolimus whole blood concentrations were monitored by microparticle enzyme immunoassay. Our goal was to maintain a blood tacrolimus level of 10-20 microg/ml. Once patients were tolerating oral medications, tacrolimus infusion was converted to oral dosing using a 4:1 conversion. Dose of tacrolimus and resulting tacrolimus concentrations were recorded and the total body clearance of tacrolimus was calculated retrospectively. The mean clearance, based on first steady-state tacrolimus concentrations necessary for achieving a therapeutic level (10-20 microg/ml), was 108.1 ml/h/kg (range 79.7-142.0 ml/h/kg), greater than that reported in adult BMT patients (71 +/- 34 ml/h/kg). The average dose required to achieve that therapeutic range was 0.0354 mg/kg/day as an intravenous continuous infusion. Over the entire course of intravenous tacrolimus, mean clearance was 97.0 ml/h/kg (range 33.4-153.3 ml/h/kg). In six of the seven patients, clearance values dropped after 2-4 weeks of therapy by an average of 32.5 ml/h/kg. In two patients, sharp drops in clearance were temporally related to changes in liver function tests. Three of the seven patients died of severe acute GVHD; all these had undergone matched unrelated donor transplantation, and two of these three had initial clearance levels over 120 ml/h/kg. Thus, children appear to have more rapid tacrolimus clearance than adults and may need to begin therapy earlier in order to obtain stable and optimal levels. More studies are needed to confirm these preliminary results.