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Efficacy and Safety of Once-Daily LCP-Tacrolimus Versus Twice-Daily Immediate-Release Tacrolimus in Adult Hispanic Stable Kidney Transplant Recipients: Sub-Group Analysis from a Phase 3 Trial.

ABSTRACT: BACKGROUND The pharmacokinetics and metabolism of tacrolimus, an immunosuppressant commonly used to prevent transplant rejection, can differ in specific subpopulations. This analysis examined treatment outcomes and safety of immediate-release tacrolimus (IR-Tac) and LCP-tacrolimus (LCPT) in stable Hispanic kidney transplant recipients. MATERIAL AND METHODS This was a post hoc analysis of clinical trial data from Hispanic adult stable kidney transplant recipients randomized to remain on IR-Tac or convert from IR-Tac to a reduced dose of LCPT (NCT00817206). Composite treatment failure was evaluated at 12 months. Estimated glomerular filtration rate and tacrolimus trough concentrations were evaluated over 12 months. RESULTS Fifty-five stable (LCPT n=26, IR-Tac n=29) kidney transplant recipients who self-identified as Hispanic or Latino were included in this analysis. Composite treatment failure occurred in 1 patient (4%) who converted to LCPT and 1 (3%) who remained on IR-Tac. The estimated glomerular filtration rate was stable over time and similar in the 2 treatment groups (P=0.08). Tacrolimus trough levels for both groups were similar over time in the 2 treatment groups (P=0.98). Treatment-emergent adverse events were similar in patients who converted to LCPT and in those who remained on IR-Tac. CONCLUSIONS Efficacy and safety were similar in Hispanic kidney transplant recipients who converted from IR-Tac to LCPT and in those remaining on IR-Tac.

SUBMITTER: Faravardeh A

PROVIDER: S-EPMC8056872 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Prevalence of immunosuppressant nonadherence in renal transplant recipients is high despite negative clinical outcomes associated with nonadherence. Simplification of dosing has been demonstrated to improve adherence in renal transplant recipients as measured through electronic monitoring and self-report. Objective:The purpose of this study was to replicate and extend previous findings by measuring adherence with multiple methods in a Canadian sample. Design:The study design was a randomized controlled medication dosing trial in adult renal transplant patients. The trial length was 4 months. Setting:This study was conducted within the Solid Organ Transplant (SOT) Clinic at Vancouver General Hospital (VGH; Vancouver, Canada). Patients:A total of 46 adult renal recipients (at least 1 year post-transplant) were recruited through the SOT clinic. With 8 withdrawals, 38 individuals completed all phases of the study. Measurements:Medication adherence was measured for a period of 4 months using multiple methods, including electronic monitoring (MEMS [Medication Event Monitoring System]), pharmacy refill data (medication possession ratio [MPR]), and by self-report using the Adherence subscale of the Transplant Effects Questionnaire (TEQ). Methods:Participants were randomized to twice-daily (n = 19) or once-daily tacrolimus dosing (n = 19) and followed over a 4-month period via monthly clinic study visits. Comparisons between the treatment groups were performed using the Mann-Whitney U and chi-square tests, for continuous and categorical variables, respectively. Results:As outlined in Table 3, the once-daily dosing group showed significantly better MEMS Dose Adherence (P = .001), whereas MEMS Timing Adherence showed a tendency toward better adherence for this group, but was not significant (P = .052). MEMS Days Adherent (P = .418), MPR% (P = .123), and self-reported adherence (P = .284) did not differ between the once- and twice-daily dosing groups when measured as continuous variables. The MPR% was significantly better for the once-daily dosing group when measured dichotomously but not continuously (P = .044). Notably, most of those exposed to once-daily dosing (63.2%) preferred this to the twice-daily regimen. Limitations:Limitations included small sample size and short follow-up period, precluding the examination of clinical outcome differences. Conclusions:Results for dose adherence replicate the finding that dose simplification increases adherence to immunosuppressants as measured through electronic monitoring. Such an advantage for the once-daily dosing group was not seen across the 2 other electronic monitoring measurement variables (days and timing adherence). This study extends previous research by examining adherence in once versus twice-daily dosing via prescription refill data in a Canadian sample. Given the gravity of potential health outcomes associated with nonadherence, although results indicate inconsistencies in significance testing across measurement methods, the medium to large effect sizes seen in the data favoring better adherence with once-daily dosing provide an indication of the potential clinical significance of these findings. Trial registration:This study was registered with ClinicalTrials.gov (NCT01334333) on April 11, 2011.

Project description:BACKGROUND:Tacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD. METHODS:A cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA. RESULTS:Conversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p?=?0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort. CONCLUSIONS:The CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements. TRIAL REGISTRATION:Clinical trials.gov identifier: NCT01884480.

Dataset Information

Efficacy and Safety of Once-Daily LCP-Tacrolimus Versus Twice-Daily Immediate-Release Tacrolimus in Adult Hispanic Stable Kidney Transplant Recipients: Sub-Group Analysis from a Phase 3 Trial.

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