Factors Affecting Day-to-Day Variations in Tacrolimus Concentration among Children and Young Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Tacrolimus is widely used as prophylaxis for graft-versus-host disease (GVHD) in allogeneic stem cell transplantation (allo-HSCT). It has a narrow therapeutic index range. High tacrolimus concentrations are associated with toxicity, while low concentrations are associated with an increased risk of GVHD. Although dose adjustments based on therapeutic drug monitoring are performed, unexpected large variations in tacrolimus concentration are sometimes encountered. Thus far, the available evidence suggests that the factors affecting tacrolimus concentration are not fully understood. This study was primarily aimed at investigating the factors affecting day-to-day variations in tacrolimus concentration among children and young adults who received continuous tacrolimus infusion after allo-HSCT. The secondary objective was identifying the factors causing large variations (> 20%) in tacrolimus concentrations. This was a retrospective cohort study of 123 consecutive pediatric and young adult patients, aged < 25 years, who received continuous intravenous tacrolimus infusion after allo-HSCT at Shinshu University Hospital, Matsumoto, Japan, between January 2009 and December 2021. To compare day-to-day variations in tacrolimus concentrations without consideration of the tacrolimus dose, two consecutive days when the tacrolimus dose was not changed were selected from the first day when the tacrolimus concentration was higher than 7 ng/mL after allo-HSCT to day 28 after allo-HSCT. Subsequently, information for the following 24-h was collected in addition to the tacrolimus concentrations and hematocrit values. Tacrolimus concentration was determined using whole blood samples. Tacrolimus concentrations significantly increased in patients who received red blood cell concentrate (RCC) transfusion (p < 0.0001) and methotrexate (p = 0.0162), patients with persistent fever (p = 0.0056), and patients with a decline in fever (p = 0.0003). In contrast, tacrolimus concentrations decreased significantly in patients who received platelet concentrate (PC) transfusion (p < 0.0001), redeveloped fever (p = 0.0261), and received replaced tacrolimus administration route set (p = 0.0008). Variations in tacrolimus concentration significantly correlated with variations in hematocrit (r = 0.556, p < 0.0001). Body weight (p < 0.0001), RCC transfusion (p < 0.0001), methotrexate use (p = 0.0333), persistent fever (p = 0.0150), and decline in fever (p = 0.0073) were associated with a sharp increase in tacrolimus concentration. In contrast, body weight (p < 0.0001), PC transfusion (p = 0.0025), and replacement of the tacrolimus administration route set (p = 0.0025) were associated with a sharp decrease in tacrolimus concentration. RCC and PC transfusions, fever, methotrexate administration, and replacement of the tacrolimus administration route set were independent factors affecting day-to-day variations in tacrolimus concentration. In addition to these factors, low body weight was a risk factor for both a sharp increase and decrease in tacrolimus concentration. These findings suggest the need for better control of tacrolimus concentrations using whole blood samples.