Understanding the importance of racial diversity in the development and implementation of pharmacogenomic guidelines in kidney transplant patients receiving tacrolimus

Tacrolimus is a commonly prescribed immunosuppressant used to prevent organ rejection. Multiple studies show CYP3A5 genotype is associated with tacrolimus serum concentration. However, in clinical settings tacrolimus is still dosed using a trial and error method with frequent trough concentration monitoring. Our study investigated the projected clinical benefit of implementing pharmacogenomics guidelines in tacrolimus dosing among kidney transplant patients. The primary outcome was acute rejection at one month post kidney transplant. Variables impacting trough level were simulated (e.g. age, body mass index, steroid use, panel reactive antibody present, genotype, number of human leukocyte antibodies mismatch). Simulated populations were analyzed under three different dosing scenarios: weight based dosing, pharmacogenomics based dosing accounting for CYP3A5 *1 and *3 alleles, and comprehensive pharmacogenomics based dosing accounting for CYP3A5 *1, *3, *6, and *7. Under all scenarios, the percentage of populations experiencing acute rejection was slightly higher in European Americans (4.5-7.6%) compared to African Americans (3.3-6.3%), with acute rejection rates lowest under our pharmacogenomics dosing scenarios (African Americans: 3.3-5.9%, European Americans: 4.5-7.5%) compared to weight based dosing (African Americans: 5.1-6.3%, European Americans: 6.2-7.6%). African Americans achieved the highest percent of the population in the targeted trough level (8-12ng/ml) using a dose of 0.1 mg/kg/day (35.2-41.1% compared to 36.4-39.0%) whereas European Americans achieved the greatest proportion in the target range using a dose of 0.125 mg/kg/day (41.5-42.1% compared to 26.7-41.2%). Our study demonstrated that African and European Americans achieved a higher percentage of patients within target trough levels using different dosing algorithms, suggesting that maximizing the clinical benefit of precision medicine requires investigating race specific dosing algorithms. Furthermore, we found African Americans had a reduced risk of acute rejection compared to European Americans, which contradicts current data. Given that our study assigned a consistent dosing level to all participants at baseline, this suggests that the higher rates of rejection in African Americans may be explained by the higher levels of interindividual dose variability seen in African Americans based on current weight based dosing algorithms. This further emphasizes the need to achieve accurate dosing levels early in treatment, a goal which can be accomplished more effectively with the use of pharmacogenomics-based dosing.Doctor of Pharmac