Age-Related Trend in Tacrolimus Clearance Among Children Undergoing Stem Cell Transplantation

Abstract

<h3>Background</h3> An optimization of tacrolims (TAC) treatment is a key to prevent graft-versus-host disease. Previous studies reported that a high clearance (CL) of TAC is a risk factor in adult with renal transplantation. However, there is limited information on the pharmacokinetics of TAC in children after hematopoietic stem cell transplantation (HSCT). The purpose of this study is to evaluate an age-dependent variation in CL of TAC. <h3>Methods</h3> We retrospectively analyzed CL of TAC in patients who underwent HSCT at the National Center for Child Health and Development in Japan from August 2006 to August 2019. There were four time points after HSCT to calculate CL of TAC; 17 hours after the start of TAC infusion (CLinitial), the first day at a steady state (CLss), 21 days after SCT (CL21), and the day before switch from intravenous infusion to oral administration (CLpre). We compared CL of TAC between children aged < 6 years and aged ≥ 6 years. TAC was infused intravenously at initial dosage of 0.02 mg/kg/day. For patients receiving voriconazole, initial dosage of TAC was adjusted to 0.01 mg/kg/day. <h3>Results</h3> A total number of 41 patients (age < 6 years; 25 patients, age ≥ 6years; 16 patients) were evaluated. Median age was 3 years (2 months - 18 years). Two patients recieved HSCT multiple time. Thirteen patients underwent HSCT for nonmalignant disease. CL of TAC in patients aged < 6 years old was significantly higher than aged ≥ 6years old at CLinitial, CLss, and CLpre.(CLinitial: 0.14 ± 0.08L/h/kg vs 0.08 ± 0.03L/h/kg (P=0.01), CLss: 0.06 ± 0.03L/h/kg vs 0.05 ± 0.02L/h/kg (P=0.04), CLpre: 0.06 ± 0.04L/h/kg vs 0.04 ± 0.02L/h/kg (P=0.03)) (Figure). The average duration was 5.4 days at the first steady state in both groups. In patients aged < 6 years old, rate of achieving the target range (10-15ng/mL) at CLss were lower than aged ≥ 6years old (76.0% vs 93.8% (p=0.045)), and 1.3 times of initial TAC dosage was needed at CLss for children aged < 6 years. <h3>Conclusion</h3> This study suggested that children aged < 6 years old need higher dosage to achieve therapeutic TAC level compared with children aged ≥ 6years old, especially at early phase of HSCT. In addition, careful TAC monitoring with consideration of age-related variation in clearance is required after pediatric HSCT.