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

Background 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. Objective To determine whether age and CYP3A5 genotype‐guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations. Setting Single hospital‐based transplant center. Methods 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 > 6 years) and randomized (2:1) after transplant to receive genotype‐guided (n = 35) or standard (n = 18) starting dose of tacrolimus for 36‐48 hours and were followed for 30 days. Results 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. Conclusions CYP3A5 genotype‐guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out‐of‐range concentrations.