Pharmacogenomics
Given the narrow therapeutic index, personalized medicine can be beneficial with the use of tacrolimus. Single nucleotide polymorphisms (SNPs) in the CYP3A5 gene can influence tacrolimus drug concentrations.[5] The mutation of G6986A produces the CYP3A5*3 allele. Those who are homozygotes for CYP3A5*3 (CYP3A5*3/*3) are considered non-expressers, and lose their functional enzyme. Expression of CYP3A5*1 (CYP3A5*1/*1, CYP3A5*1/3) leads to a higher enzymatic activity and metabolism of tacrolimus.[7] CYP3A5*1 expressers may require two-fold higher doses of tacrolimus to achieve therapeutic blood targets.[5]
In May 2018, a study by Min and colleagues evaluated a new way of dosing tacrolimus based on a patient's genotype. They compared genotype-guided dosing to standard dosing of tacrolimus in pediatric patients receiving heart, kidney, or liver transplant. The goal was to compare time to achieve and maintain therapeutic tacrolimus trough concentrations between the two groups. Patients were categorized as being CYP3A5 expressers or non-expressers, then randomized after transplantation to receive either genotype-guided dosing (n=35) or standard dosing (n=18) for tacrolimus. Those who were in the genotype-guided dosing group were dosed based on a sliding scale algorithm, with the lowest dose in older patients (more than 6 years of age) who were CYP3A5 non-expressers and the highest dose in younger children (less than 6 years) who were CYP3A5 expressers. Patients were followed for 30 days after initiation.
Patients in the genotype-guided dosing arm achieved therapeutic tacrolimus concentrations earlier than those in the standard clinical dosing arm, with the median time to first therapeutic concentration of 3.4 (range 2.5–6.6) days in the genotype-guided arm and 4.7 (3.5–8.6) days in the standard arm (p=0.049). In the genotype-guided group, 69% of patients achieved stable tacrolimus concentrations, while only 44% of patients in the standard arm achieved stable concentrations within 30 days (p=0.089).
The median time to achieve stable therapeutic concentrations was 18 (range 14–27) days in the genotype-guided arm. This median time could not be calculated in the standard arm because < 50% of participants achieved stable therapeutic concentrations during study follow-up.[5] This study indicates that genotype-guided dosing could be a favorable approach to tacrolimus initiation.
Pediatr Pharm. 2018;24(12) © 2018 University of Virginia
