Tacrolimus clearance is age-dependent within the pediatric population

Abstract

For prevention of graft-versus-host disease, the consensus initial intravenous dose of tacrolimus for adults is 0.03 mg/kg/day. Whether target whole blood concentrations of tacrolimus in children undergoing hematopoietic stem cell transplantation can be achieved reproducibly with this dose is not known. We reviewed the tacrolimus blood levels and calculated clearances for 55 children (aged 6 months to 18 years, median 9 years) using tacrolimus after allogeneic marrow, blood stem cell or cord blood transplantation. The tacrolimus dose regimen was 0.03 mg/kg/day by continuous infusion starting on day -1 or day -2. At the first sampling in the peritransplant period, 71% of the tacrolimus blood levels were within the target range of 5-15 ng/ml, 87% were in the safe range of 5-20 ng/ml, 9% were toxic, and 4% were subtherapeutic. Twenty-five children were converted to oral drug using the recommended oral/intravenous dose ratio of 4.0. At the first sampling after oral conversion, 80% were in the target range, and 20% were subtherapeutic. Clearance of tacrolimus was calculated from the blood levels for patients during intravenous dosing and normalized by ideal body weight. There was a decreased clearance over the first 2 weeks only for the children >12 years old (P = 0.014). The initial calculated clearances of tacrolimus did not differ between age groups, but at steady state the mean tacrolimus clearance (+/- s.d.) was higher for those <6 years old (0.159+/-0.082 l/h/kg) than for those 6-12 years old (0.109+/-0.053 l/h/kg) or >12 years old (0.104 +/-0.068 l/h/kg). Children <6 years old undergoing hematopoietic stem cell transplantation have a higher weight-normalized tacrolimus clearance than older children and adults, and careful therapeutic monitoring is needed in the first 2 weeks after transplantation to avoid prolonged subtherapeutic dosing for this age group.