Related Experiment Videos
Tacrolimus clearance is age-dependent within the pediatric population
D Przepiorka1, D Blamble, S Hilsenbeck
1Baylor College of Medicine Center for Cell and Gene Therapy, Houston, Texas 77030, USA.
Insights
Pediatric hematopoietic stem cell transplant patients require careful tacrolimus monitoring. Younger children (<6 years) exhibit higher drug clearance, necessitating dose adjustments to maintain therapeutic levels and prevent subtherapeutic dosing.
Area of Science:
- Pharmacology
- Pediatric Hematology
- Immunosuppression
Background:
- Graft-versus-host disease (GVHD) prevention is critical post-hematopoietic stem cell transplantation (HSCT).
- Tacrolimus is a key immunosuppressant, with established adult dosing guidelines.
- Pediatric tacrolimus dosing efficacy and reproducibility remain less understood.
Purpose of the Study:
- To evaluate the achievement of target whole blood tacrolimus concentrations in children undergoing HSCT using the standard adult initial dose.
- To analyze tacrolimus pharmacokinetics, including clearance, in pediatric HSCT recipients across different age groups.
- To assess the safety and efficacy of tacrolimus dosing in children post-HSCT.
Main Methods:
- Retrospective review of 55 pediatric HSCT patients (6 months to 18 years).
- Analysis of tacrolimus blood levels and calculation of drug clearance during intravenous and oral administration.
- Comparison of tacrolimus levels and clearance across pediatric age strata.
Main Results:
- 71% of children achieved target tacrolimus levels (5-15 ng/ml) initially with intravenous dosing.
- 87% were within the safe range (5-20 ng/ml), with 9% toxic and 4% subtherapeutic levels.
- Younger children (<6 years) demonstrated significantly higher weight-normalized tacrolimus clearance compared to older children and adults.
Conclusions:
- The standard initial intravenous dose of tacrolimus may not consistently achieve therapeutic concentrations in all pediatric HSCT patients.
- Younger children (<6 years) exhibit higher tacrolimus clearance, requiring closer monitoring and potential dose adjustments.
- Therapeutic drug monitoring is crucial in the initial peritransplant period, especially for young children, to optimize immunosuppression and prevent GVHD.
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.