Work

Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

Year: 2017

Type: article

Abstract: BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. STUDY DESIGN: Randomized prospective crossover study. SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing. INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. OUTCOMES: ), time to peak concentration, and bioavailability of LCPT versus IR-Tac, according to CYP3A5 genotype. MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. RESULTS: was 33% higher in CYP3A5 expressers compared with nonexpressers (P=0.04): With LCPT, this difference was 11% (P=0.4). LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922.

Source: American Journal of Kidney Diseases

DOI: 10.1053/j.ajkd.2017.07.018