Once-Daily Extended-Release Versus Twice-Daily Standard-Release Tacrolimus in Kidney Transplant Recipients: A Systematic Review [feedly]

 
 

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Once-Daily Extended-Release Versus Twice-Daily Standard-Release Tacrolimus in Kidney Transplant Recipients: A Systematic Review

Background: A simplified dosing regimen may improve drug compliance in kidney transplant recipients and long-term graft outcomes. We aimed to identify, appraise, and synthesize the current evidence comparing the relative safety and efficacy of the recently introduced daily versus standard twice-daily tacrolimus administration. Methods: We systematically reviewed all randomized controlled trials and observational studies that compared the outcomes of daily versus twice-daily tacrolimus formulation in kidney transplant recipients. Medline (from 1948 to July week 4 2011), Embase (1980 to 2011 week 31), the Cochrane Library (1991 to June 2011), and conference proceedings were searched without language restriction. Results: Six randomized controlled trials (n=2499) and 15 observational studies (n=2886) were included in the review. There were no significant differences in biopsy-proven acute rejection (two trials, n=1093; risk ratio [RR; confidence interval (CI)], 1.24 [0.93-1.65]; P=0.15; I2=0%), patient survival (three trials, n=1156; RR [CI], 0.99 [0.97-1.02]; P=0.55; I2=32%), and graft survival (three trials, n=1156; RR [CI], 0.99 [0.97-1.02]; P=0.67; I2=0%) between the two formulations at 12 months. Similar results for acute rejection (five studies, n=391; RR [CI], 0.99 [0.93-1.06]; P=0.84; I2=0%) and overall patient survival (two studies, n=218; RR [CI], 1.02 [0.94-1.10]; P=0.62; I2=0%) were observed in observational studies. Conclusions: Once-daily tacrolimus appears to be as effective as twice-daily tacrolimus up to 12 months after kidney transplantation. (C) 2013 Lippincott Williams & Wilkins, Inc.

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A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients

A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC_0-12h and peak concentration (C_max) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC_0-12h and 1.09 (90% CI 101-118%, p = 0.057) for C_max. Mean (SD) C₀ was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.

Tacrolimus-Based, Steroid-Free Regimens in Renal Transplantation: 3-Year Follow-Up of the ATLAS Trial

Tacrolimus-Based, Steroid-Free Regimens in Renal Transplantation: 3-Year Follow-Up of the ATLAS Trial

Background: Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods: This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results: Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion: Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

The Once-Daily Formulation of Tacrolimus: A Step Forward in Kidney Transplantation?

The Once-Daily Formulation of Tacrolimus: A Step Forward in Kidney Transplantation?: Nonadherence is a critical issue in transplantation. Recently, Astellas designed a once-daily-extended release formulation of tacrolimus (Tac). Despite initial reports showing bioequivalence of Tac once-daily (Advagraf) with the original formulation requiring twice-daily intake (Tac twice-daily, Prograf), several groups have now shown a sustained decrease in Tac exposure upon conversion from Prograf to Advagraf. Here, we discuss the possible reasons for this observation and how it could affect the expected benefits of Advagraf, and we comment on the fact that a similar lack of bioequivalence might prevail with generic immunosuppressive drugs.

A Randomized Trial With Steroids and Antithymocyte Globulins Comparing Cyclosporine/Azathioprine Versus Tacrolimus/Mycophenolate Mofetil (CATM2) in Renal Transplantation

A Randomized Trial With Steroids and Antithymocyte Globulins Comparing Cyclosporine/Azathioprine Versus Tacrolimus/Mycophenolate Mofetil (CATM2) in Renal Transplantation: Background: The best immunosuppressive regimen in benefit-risk ratio in renal transplantation is debated. Nowadays, tacrolimus (Tac) and mycophenolate mofetil (MMF) are considered more efficient than cyclosporine A (CsA) and MMF, but recent studies have challenged this assumption.
Methods: We conducted a monocentric, prospective, open-labeled, randomized, and controlled trial comparing CsA/azathioprine (Aza) versus Tac/MMF in 289 kidney transplant recipients treated with antithymocyte globulins and prednisone. Primary outcome was the number of patients with clinically suspected acute rejection at 1 year. Secondary outcomes were the number of patients with biopsy-proven acute rejection (BPAR), estimated glomerular filtration rate (eGFR), patient and graft survivals, and adverse events at 1 and 3 years.

Impact of Early Conversion From Tacrolimus to Sirolimus on Chronic Allograft Changes in Kidney Recipients on Rapid Steroid Withdrawal

Impact of Early Conversion From Tacrolimus to Sirolimus on Chronic Allograft Changes in Kidney Recipients on Rapid Steroid Withdrawal: Background. Calcineurin-inhibitor therapy is a contributing factor to the origin of interstitial fibrosis and tubular atrophy (IFTA).
Methods. We conducted a prospective randomized trial of conversion of tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal. We compared the chronic changes (IFTA and sum of Banff chronic scores—Total Score) on protocol biopsies at 1 month, 1 year, and 2 years in all randomized patients. We compared the outcomes between treatment groups and analyzed the impact of previous rejection on the chronic changes.

Kidney Transplantation With Minimized Maintenance: Alemtuzumab Induction With Tacrolimus Monotherapy—An Open Label, Randomized Trial

Kidney Transplantation With Minimized Maintenance: Alemtuzumab Induction With Tacrolimus Monotherapy—An Open Label, Randomized Trial: Background. Immunosuppressive regimens for kidney transplantation which reduce the long-term burden of immunosuppression are attractive, but little data are available to judge the safety and efficacy of the different strategies used. We tested the hypothesis that the simple, cheap, regimen of alemtuzumab induction combined with tacrolimus monotherapy maintenance provided equivalent outcomes to the more commonly used combination of interleukin-2 receptor monoclonal antibody induction with tacrolimus and mycophenolate mofetil combination maintenance, both regimens using steroid withdrawal after 7 days.

Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal

Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal: Background. The use of calcineurin inhibitors is associated with chronic nephrotoxicity and lower glomerular filtration rate (GFR). As a result, one strategy of transplant immunosuppression is calcineurin inhibitor elimination.
Methods. The aim of this study was to determine the outcome of a prospective randomized trial of kidney transplant recipients receiving rapid corticosteroid withdrawal, tacrolimus and mycophenolate mofetil (MMF) for 1 month followed by randomization to switch to sirolimus-MMF or to stay on tacrolimus-MMF. The primary outcome was the difference in measured GFR at 1 year using intention-to-treat analysis.

The PROMISE Study: A Phase 2b Multicenter Study of Voclosporin (ISA247) Versus Tacrolimus in De Novo Kidney Transplantation

The PROMISE Study: A Phase 2b Multicenter Study of Voclosporin (ISA247) Versus Tacrolimus in De Novo Kidney Transplantation:

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates.

Randomized Trial of Immunosuppressive Regimens in Renal Transplantation

Randomized Trial of Immunosuppressive Regimens in Renal Transplantation:
The optimal long-term regimen for immunosuppression for kidney transplant recipients is unknown. We conducted a randomized trial involving 150 kidney transplant recipients to compare tacrolimus/sirolimus, tacrolimus/mycophenolate mofetil (MMF), and cyclosporine/sirolimus. All patients received daclizumab induction and maintenance corticosteroids. Median follow-up was 8 yr post-transplant.

Kidney Transplantation With Minimized Maintenance: Alemtuzumab Induction With Tacrolimus Monotherapy-An Open Label, Randomized Trial

Kidney Transplantation With Minimized Maintenance: Alemtuzumab Induction With Tacrolimus Monotherapy-An Open Label, Randomized Trial: Background. Immunosuppressive regimens for kidney transplantation which reduce the long-term burden of immunosuppression are attractive, but little data are available to judge the safety and efficacy of the different strategies used. We tested the hypothesis that the simple, cheap, regimen of alemtuzumab induction combined with tacrolimus monotherapy maintenance provided equivalent outcomes to the more commonly used combination of interleukin-2 receptor monoclonal antibody induction with tacrolimus and mycophenolate mofetil combination maintenance, both regimens using steroid withdrawal after 7 days.

Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal

Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal: "Background. The use of calcineurin inhibitors is associated with chronic nephrotoxicity and lower glomerular filtration rate (GFR). As a result, one strategy of transplant immunosuppression is calcineurin inhibitor elimination.
Methods. The aim of this study was to determine the outcome of a prospective randomized trial of kidney transplant recipients receiving rapid corticosteroid withdrawal, tacrolimus and mycophenolate mofetil (MMF) for 1 month followed by randomization to switch to sirolimus-MMF or to stay on tacrolimus-MMF. The primary outcome was the difference in measured GFR at 1 year using intention-to-treat analysis.

A Multicenter Experience With Generic Tacrolimus Conversion

A Multicenter Experience With Generic Tacrolimus Conversion: "Background. The first generic tacrolimus product gained Food and Drug Administration approval in August 2009. This prospective, observational trial sought to determine the need for dose titrations and measure drug cost savings on conversion to generic tacrolimus.
Methods. Transplant recipients on stable tacrolimus doses were converted from brand to generic tacrolimus on a mg:mg basis. Data were collected at the time of generic conversion (study arm) and at a time point exactly 6 months before conversion (control arm) for all subjects.

Efficacy and Safety of Conversion from Twice-daily to Once-daily Tacrolimus in a Large Cohort of Stable Kidney Transplant Recipients

Efficacy and Safety of Conversion from Twice-daily to Once-daily Tacrolimus in a Large Cohort of Stable Kidney Transplant Recipients: "

Prolonged-release tacrolimus was developed to provide a more convenient once-daily dosing that could improve patient adherence. We conducted a multicenter, prospective, observational, 12-month study to describe the efficacy, safety and patient preference of conversion from tacrolimus twice-daily to once-daily formulation in stable kidney transplant recipients in routine clinical practice. Conversion was made on a 1 mg: 1 mg basis (1 mg: 1.1 mg in patients with trough levels <6 ng/mL).

The ORION Study: Comparison of Two Sirolimus-Based Regimens versus Tacrolimus and Mycophenolate Mofetil in Renal Allograft Recipients

The ORION Study: Comparison of Two Sirolimus-Based Regimens versus Tacrolimus and Mycophenolate Mofetil in Renal Allograft Recipients: "

Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor-terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients.

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The Impact of Conversion From Prograf to Generic Tacrolimus in Liver and Kidney Transplant Recipients With Stable Graft Function.

The Impact of Conversion From Prograf to Generic Tacrolimus in Liver and Kidney Transplant Recipients With Stable Graft Function.: "Momper JD, Ridenour TA, Schonder KS, et al.
The Impact of Conversion From Prograf to Generic Tacrolimus in Liver and Kidney Transplant Recipients With Stable Graft Function. [JOURNAL ARTICLE]
Am J Transplant 2011 Jun 30.
Abstract | Full Citation | Publisher Full Text | Find Related Articles "

Sotrastaurin, a Novel Small Molecule Inhibiting Protein-Kinase C: Randomized Phase II Study in Renal Transplant Recipients

Sotrastaurin, a Novel Small Molecule Inhibiting Protein-Kinase C: Randomized Phase II Study in Renal Transplant Recipients: "

Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81).

Comparable Renal Function at 6 Months with Tacrolimus Combined with Fixed-Dose Sirolimus or MMF: Results of a Randomized Multicenter Trial in Renal Transplantation

Comparable Renal Function at 6 Months with Tacrolimus Combined with Fixed-Dose Sirolimus or MMF: Results of a Randomized Multicenter Trial in Renal Transplantation: "In a multicenter trial, renal transplant recipients were randomized to tacrolimus with fixed-dose sirolimus (Tac/SRL, N = 318) or tacrolimus with MMF (Tac/MMF, N = 316). Targeted tacrolimus trough levels were lower in the Tac/SRL group after day 14. The primary endpoint was renal function at 6 months using creatinine clearance (Cockcroft-Gault) and was comparable at 66.4 mL/min (SE 1.4) with Tac/SRL and at 65.2mL/min (SE 1.3) with Tac/MMF (completers). Biopsy-confirmed acute rejection was 15.1% (Tac/SRL) and 12.3% (Tac/MMF). In both groups, graft survival was 93% and patient survival was 99.0%. Premature withdrawal due to an adverse event was twice as high in the Tac/SRL group, 15.1% versus 6.3%. Hypercholesterolemia incidence was higher with Tac/SRL (P<.05) while CMV, leukopenia, and diarrhea incidences were higher with Tac/MMF (P<.05). The incidence of any antidiabetic treatment for >30 consecutive days in previously nondiabetic patients was 17.8%, Tac/SRL, and 24.8%, Tac/MMF. Evaluation at 6 months showed comparable renal function using tacrolimus/sirolimus and tacrolimus/MMF regimens."