Risk Factors for Subtherapeutic Tacrolimus Levels after Conversion from Continuous Intravenous Infusion to Oral in Children after Allogeneic Hematopoietic Cell Transplantation

Abstract

Tacrolimus (FK506) is a calcineurin inhibitor and is an essential component of many immunosuppressive regimens. The oral bioavailability of tacrolimus may be affected by many factors, including patient age and gender, as well as by drug-drug interactions or genetic polymorphisms in drug metabolism. The dosing recommendations for pediatric allogeneic hematopoietic cell transplantation (alloHCT) recipients have been derived from tacrolimus use in adult solid-organ transplantation patients. Data describing the impact of conversion of i.v. tacrolimus to oral on the incidence of acute graft-versus-host disease (aGVHD) are limited in children after alloHCT. In this study, we describe the incidence of grades II to IV aGVHD after conversion from i.v. tacrolimus to oral tacrolimus and study the clinical factors associated with delayed achievement of therapeutic blood levels. In this retrospective analysis, 68 pediatric patients (median age, 6.7 years; range, .25 to 22 years), underwent alloHCT for malignant and nonmalignant diseases and received tacrolimus and mycophenolate mofetil for aGVHD prophylaxis. Among all patients, the median number of days to achieve therapeutic tacrolimus trough concentration (10 ng/mL to 20 ng/mL) was 7 days (range, 0 to 37 days). Twenty-two patients developed grades II to IV aGVHD and the cumulative incidence of grades II to IV aGVHD in all patients was 32.4% (standard error, .06). On multivariate analysis ethnicity (white versus others: odds ratio [OR], −4.5; 95% confidence interval [95% CI], 1.091 to 18.91; P = .038) and ≥ 10 days of subtherapeutic tacrolimus levels in first 30 days on i.v. (OR, −3.8; 95% CI, 1.276 to 11.43; P = .017) were significantly associated with delay in achieving therapeutic tacrolimus trough concentration. The impact of race/ethnicity on therapeutic tacrolimus trough concentration in pediatric alloHCT recipients should be further studied prospectively so that individualized dosing plans can be developed.