A randomized clinical trial of age and genotype-guided tacrolimus dosing after pediatric solid organ transplantation.

Abstract

Tacrolimus pharmacokinetics are influenced by age and CYP3A5 genotype with CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) being fast metabolizers. However, the benefit of genotype-guided dosing in pediatric solid organ transplantation has been understudied. To determine whether age and CYP3A5 genotype-guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations. Single hospital-based transplant center. This was a randomized, semi-blinded, 30-day pilot trial. Between 2012 and 2016, pediatric patients listed for solid organ transplant were consented and enrolled into the study. Participants were categorized as expressors, CYP3A5*1/*1 or CYP3A5*1/*3, and nonexpressors, CYP3A5*3/*3. Patients were stratified by age (≤ or > 6years) and randomized (2:1) after transplant to receive genotype-guided (n=35) or standard (n=18) starting dose of tacrolimus for 36-48hours and were followed for 30days. Median age at transplant in the randomized cohort was 2.1 (0.75-8.0) years; 24 (45%) were male. Participants in the genotype-guided arm achieved therapeutic concentrations earlier at a median (IQR) of 3.4 (2.5-6.6)days compared to those in the standard dosing arm of 4.7 (3.5-8.6) days (P=0.049), and had fewer out-of-range concentrations [OR (95% CI)=0.60 (0.44, 0.83), P=0.002] compared to standard dosing, with no difference in frequency of adverse events between the two groups. CYP3A5 genotype-guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out-of-range concentrations.