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Median estimated glomerular filtration rate at 30, 90, and 365 days post-transplantation for patients who received extended-release (N = 19) or immediate-release
Source publication
Introduction
Real-world data with extended-release tacrolimus (ER-T) are lacking in the USA. This study examined clinical outcomes and healthcare resource utilization in kidney transplant patients receiving ER-T in clinical practice.
Methods
This was a retrospective, single-center analysis (February–June 2016) using data from Northwestern Universi...
Context in source publication
Context 1
... Mean eGFR ranged between 46.2 and 52.6 mL/min/1.73 m 2 across time points and treatment groups. The values were similar in both treatment groups at 30, 90, and 365 days post-transplantation (p = 0.71, p = 0.51, and p = 0.47, respectively), the caveat being that data were capped when patients achieved the maximum eGFR of 60 mL/min/1.73 m 2 (Fig. ...
Citations
... Extended-release TAC is associated with improvements in medication adherence, potentially achieving better outcomes (Guirado et al., 2011;Kuypers et al., 2013). Depending on the institutional guidelines and experience, the post-transplantation period can be started with extended-release capsules or alternatively with immediate-release capsules switching later to extended-release capsules, displaying similar clinical outcomes during the first year (Ho et al., 2019). ...
... Extended-release TAC capsules were developed later than immediate-release capsules and approved by FDA in 2013. For this reason, multi-center studies and extensive reports have provided strong recommendations regarding immediate-release capsules, while increasing evidence has demonstrated that extended-release capsules are an advisable option as we pretended to explore in this study because they are easier to administer and improve patients' adherence with the same efficacy (Ho et al., 2013;Meçule et al., 2019). ...
Background: Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C0) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, but sampling is challenging in pediatric patients. Limited-sampling strategies (LSS) have been developed to estimate AUC. Herein, we aimed to determine AUC(0–24) and CYP3A5 genotype in Chilean pediatric kidney recipients using extended-release TAC, to evaluate different LSS-AUC(0–24) formulas and dose requirements. Patients and methods: We analyzed pediatric kidney recipients using different extended-release TAC brands to determine their trapezoidal AUC(0–24) and CYP3A5 genotypes (SNP rs776746). Daily TAC dose (TAC-D mg/kg) and AUC(0–24) normalized by dose were compared between CYP3A5 expressors (*1/*1 and *1/*3) and non-expressors (*3/*3). We evaluated the single and combined time-points to identify the best LSS-AUC(0–24) model. We compared the performance of this model with two pediatric LSS-AUC(0–24) equations for clinical validation. Results: Fifty-one pharmacokinetic profiles were obtained from kidney recipients (age 13.1 ± 2.9 years). When normalizing AUC(0–24) by TAC-D significant differences were found between CYP3A5 expressors and non-expressors (1701.9 vs. 2718.1 ng*h/mL/mg/kg, p < 0.05). C0 had a poor fit with AUC(0–24) (r 2 = 0.5011). The model which included C0, C1 and C4, showed the best performance to predict LSS-AUC(0–24) (r 2 = 0.8765) and yielded the lowest precision error (7.1% ± 6.4%) with the lowest fraction (9.8%) of deviated AUC(0–24), in comparison to other LSS equations. Conclusion: Estimation of LSS-AUC(0–24) with 3 time-points is an advisable and clinically useful option for pediatric kidney recipients using extended-release TAC to provide better guidance of decisions if toxicity or drug inefficacy is suspected. The different CYP3A5 genotypes associated with variable dose requirements reinforce considering genotyping before KTx. Further multi-centric studies with admixed cohorts are needed to determine the short- and long-term clinical benefits.
... As an alternative, dose-related toxicities can be controlled by using long-acting injectables [5,[7][8][9][10][11][12][13][14][15][16][17][18]. Recently, two formulation prototypes were developed using poly-lactide-co-glycolide (PLGA) as the matrix material [19,20]. ...
Today, tacrolimus represents a cornerstone of immunosuppressive therapy for liver and kidney transplants and remains subject of preclinical and clinical investigations, aiming at the development of long-acting depot formulations for subcutaneous injection.
One major challenge arises from establishing in vitro-in vivo correlations due to the absence of meaningful in vitro methods predictive for the in vivo situation, together with a strong impact of multiple kinetic processes on the plasma concentration-time profile. In the present approach, two microsphere formulations were compared with regards to their in vitro release and degradation characteristics. A novel biorelevant medium provided the physiological ion and protein background. Release was measured using the dispersion releaser technology under accelerated conditions. A release of 100% of the drug from the carrier was achieved within 7 days. The capability of the in vitro performance assay was verified by the level A in vitro-in vivo correlation analysis. The contributions of in vitro drug release, drug degradation, diffusion rate and lymphatic transport on the absorption process was quantitatively investigated by means of a mechanistic modelling approach. The degradation rate, together with release and diffusion characteristics provides an estimate of the bioavailability and therefore can be a guide to future formulation development.
... The majority of exclusions were made due to the articles being abstract-only publication, as described in Fig. 1. A total of 10 observational studies, with a total number of 1176 adult de novo KTRs, were included in this meta-analysis [26][27][28][29][30][31][32][33][34][35]. ...
... The Egger's test detected no evidence of publication bias (bias, − 0.62; 95% CI − 3.74 to 2.48; p = 0.478; 4 studies, excluding 1 study with a zero rate in total). When the study in which KTRs received treatment conversion to ER-Tac from IR-Tac within 10 days post-KT [35] was excluded in the sensitivity analysis, no substantive change to the difference was observed (4 studies, n = 585; RR, 0.70; 95% CI 0.51-0.95; p = 0.02; I 2 = 0%). ...
... Two included studies reported patient survival rates within the first 6 months post-KT between KTRs who received ER-Tac and IR-Tac [27,35]. The reported patient survival rate within the first 6 months post-KT of KTRs who received ER-Tac was comparable with those who received IR-Tac (2 studies, n = 153; RR, 0.99; 95% CI 0.94-1.04; ...
Background
Tacrolimus is the most commonly prescribed medication in initial immunosuppressive regimens to prevent acute rejection in kidney transplant recipients (KTRs). Tacrolimus was originally available as an immediate-release formulation (IR-Tac) given twice daily. Extended-release tacrolimus (ER-Tac) given once daily was later developed with the expectation of improved medication adherence. Data from observational studies, which compared outcomes between ER-Tac and IR-Tac in different populations of KTRs including those who are unlikely to be enrolled in randomized clinical trials, have been reported.
Purpose
To evaluate the incidence of biopsy-proven acute rejection (BPAR) at 12 months together with other outcomes reported in observational studies among adult KTRs who received ER-Tac compared to IR-Tac.
Methods
In accordance with the recommendations of the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology, we systematically reviewed all observational studies that compared clinical outcomes between ER-Tac and IR-Tac in KTRs. The systematic searches were conducted on PubMed, EMBASE, Scopus, and Web of Science without language restriction. Reference lists were also searched and reviewed. Data were extracted for BPAR, graft survival, patient survival, estimated glomerular filtration rate (eGFR), serum creatinine (Scr), creatinine clearance (CrCl), at different times after kidney transplantation (KT). A meta-analysis was performed to integrate the results from the eligible studies. This study is registered with PROSPERO, number CRD42019135705.
Results
From the 1401 articles screened, 10 observational studies in KTRs who received tacrolimus were included. The pooled results showed significantly lower BPAR with ER-Tac than with IR-Tac at 12 months post-KT (5 studies, n = 659; RR, 0.69; 95% CI 0.51–0.95; p = 0.02; I² = 0%). No significant differences in BPAR at other time points after KT were found. Graft survival, patient survival, Scr, and eGFR were comparable between groups at different times over approximately 1 year after transplantation.
Conclusions
Based upon currently available evidence in observational studies, 30% lower risk of BPAR was observed in ER-Tac group compared with IR-Tac group at 12 months post-KT, while there was no significant difference in BPAR risk at any other studied time points. No differences in graft- and patient-survival rates and kidney function were found. Given the limitations of observational studies to make causal inference, as well as quality limitations among the included studies, caution should be exercised in interpreting these findings.
Background:
Kidney transplantation is the most important treatment for end-stage renal disease. Immunosuppressive therapies can prevent acute rejection for kidney transplant recipients. Tacrolimus is usually administered to prevent graft rejection after transplantation. Previous studies have indicated that once-daily tacrolimus may improve medication adherence. Therefore, this meta-analysis aimed to compare clinical outcomes between once-daily and twice-daily tacrolimus in de novo renal transplant patients.
Methods:
Eligible studies were identified from the Cochrane Library Database, PubMed, and Embase until July 2022. Those randomized controlled trials (RCTs) evaluating once-daily versus twice-daily tacrolimus formulations in de novo renal transplantation were included. A summary risk ratio (RR) and standardized mean difference (SMD) with the 95% confidence interval (CI) were estimated using a random-effects model.
Results:
In total, nine RCTs were included. There were no differences in biopsy-confirmed acute rejection rates between patients with once-daily and those with twice-daily tacrolimus (RR, 0.91; 95% CI, 0.73-1.13) in 12 months. Regarding renal function, there was no significant difference between the once-daily and twice-daily tacrolimus groups (SMD, -0.03; 95% CI, -0.12-0.07). In addition, the risk of graft failure, death, and adverse events in the first year was similar for the once-daily and twice-daily tacrolimus groups.
Conclusion:
Our major findings suggest that de novo renal transplantation recipients receiving once-daily tacrolimus immediately after transplantation have comparable efficacy and safety with those recipients who received twice-daily tacrolimus. Therefore, once-daily tacrolimus medication can be an alternative for de novo renal transplantation recipients.
Introduction:
Prior randomized trials and observational studies have generally reported similar outcomes in kidney transplant recipients (KTRs) treated with immediate-release tacrolimus (IR-TAC) versus extended-release tacrolimus (ER-TAC). However, many of these previous studies focused on patients with low immunological risks, had small sample sizes and brief follow-up periods, and excluded outcomes associated with graft loss, such as chronic rejection.
Methods:
To address these limitations, we conducted a cohort study of 848 KTRs at a single transplantation center who had generally high immunological risks and were treated with either IR-TAC capsules (589 patients, 65.9%) or ER-TAC capsules (289 patients, 34.1%). All patients received the same maintenance immunosuppressive regimen for at least 3 months post-transplantation. Afterwards, tacrolimus formulation was at the discretion of each patient's transplant nephrologist. For the two treatment groups, we compared the hazards of experiencing a composite outcome of acute or chronic antibody-mediated rejection (AMR), acute or chronic T-cell-mediated rejection, de novo DSA, and/or graft loss over a 3-year period starting at 3 months post-transplantation.
Results:
In a multivariable Cox proportional hazards regression model, KTRs treated with IR-TAC capsules had an increased hazard of experiencing the composite outcome when compared to patients treated with ER-TAC capsules; however, this result was not significant (adj HR 1.24, 95% CI .92-1.68, p = .163). Similar results were obtained with inverse probability of treatment weighting (IPTW) using a propensity score (adj HR 1.25, 95% CI .93-1.68, p = .146).
Conclusion:
These findings suggest that when compared to IR-TAC capsules, ER-TAC capsules do not reduce the hazard of poor outcomes in KTRs with generally high immunological risks. This article is protected by copyright. All rights reserved.
