Background: Tacrolimus is available as twice-daily Prograf�® (Tac-BID) and the once-daily formulation, Advagraf�®\n(Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve\nsimilar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily\nmetabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the\nCYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could\naccount for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD.\nMethods: A cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent\nadditional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and\npost-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified\nthrough analysis of genomic DNA.\nResults: Conversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to\n3.8 (1.3) mg/day (p = 0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose\nadjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar\nfindings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more\nhighly represented in the East Asian cohort.\nConclusions: The CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID\nto Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of\nCYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and\nethnicity in optimizing dosing requirements.
Loading....