Recipient Versus Donor CYP3A4/5 Genotypes in Adult Liver Transplant Recipients to Achieve Therapeutic Tacrolimus Concentrations Early Post-Transplant

Abstract

Tacrolimus is an immunosuppressive agent with difficult dosing due to a narrow therapeutic index and large interpatient pharmacokinetic variability, for which CYP3A5 variation plays a role. Tacrolimus/CYP3A5 pharmacogenetic guidelines exclude liver transplant patients with a donor/recipient CYP3A5 mismatch. We sought to determine the influence of donor vs. recipient CYP3A5 genotype early post-transplant and evaluate tacrolimus dosing strategies in liver transplant recipients with various recipient/donor CYP3A5 genotype combinations. This was a single-center, retrospective analysis of 58 prospectively enrolled adult liver transplant patients prescribed tacrolimus post-transplant, with donor and recipient CYP3A5 genotype data, which were categorized as recipient expresser (RE) or nonexpresser (RN) and donor expresser (DE) or nonexpresser (DN). Patients were stratified as REDE, REDN, RNDN, or RNDE with comparisons across groups. Prediction error (PE) based on predicted versus actual therapeutic dose was calculated for eight published dosing methods. Donor/recipient genotype was mismatched in 41% of liver transplant recipients. Weight-adjusted total daily dose for first therapeutic tacrolimus concentration was significantly different across CYP3A5 combinations, with recipient expressors requiring the highest doses (REDE 0.15 mg/kg/day, REDN 0.19 mg/kg/day, RNDE 0.12 mg/kg/day, RNDN 0.09 mg/kg/day, p = 0.006). Of the eight dosing methods analyzed, two performed with < 2% PE overall, and ≤ 20% PE for all four genotype combinations: one included recipient genotype only; the other included donor and recipient genotype. Collectively, our findings suggest recipient CYP3A5 genotype may be more important than donor genotype in the immediate post-liver transplant period for predicting optimal tacrolimus dosing to achieve therapeutic trough concentrations.

Keywords: CYP3A5; Prograf; liver transplant; pharmacogenetics; pharmacogenomics; precision medicine; tacrolimus.