Renal Function and Patient-Reported Outcomes in Stable Kidney Transplant Patients Following Conversion From Twice-Daily Immediate-Release Tacrolimus to Once-Daily Prolonged-Release Tacrolimus: A 12-Month Observational Study in Routine Clinical Practice in Germany (ADAGIO)

IntroductionThis 12-month, noninterventional study on routine clinical practice in Germany evaluated renal function in stable kidney transplant recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T).MethodsRenal function was assessed in 183 patients by estimated glomerular filtration rate using the modification of diet in renal disease-4 formula. Self-reported gastrointestinal health-related quality of life, adherence, satisfaction with PR-T, suspected rejection episodes, and safety were also assessed at conversion and at 3, 6, and 12 months.ResultsConversion from IR-T to PR-T resulted in stable kidney function over 12 months, with a difference in estimated glomerular filtration rate between the first and final visits of 0.1 mL/min/1.73 m² (95% confidence interval, ?1.6, 1.8). Eight patients experienced an acute rejection episode (4.4%). At each assessment, gastrointestinal health-related quality of life was low and adherence was high. Most patients reported that they were very satisfied (69.8%) or satisfied (28.1%) with PR-T at the final visit. Among patients reporting a preference, 78.4% preferred PR-T, 2.2% preferred IR-T, and 19.4% reported no preference. The safety profile of PR-T was consistent with that previously described.ConclusionConversion of stable kidney transplant recipients from IR-T to PR-T provided stable kidney and graft function over 12 months (Verband Forschender Arzneimittelhersteller--registered study: NIS ADV-02).     

Safety and Effectiveness of Conversion From Cyclosporine to Once-Daily Prolonged-Release Tacrolimus in Stable Kidney Transplant Patients: A Multicenter Observational Study in Japan

This study investigated the safety and effectiveness of conversion from cyclosporine- to prolonged-release tacrolimus (PR-T)-based immunosuppression in kidney transplant recipients (KTRs) in Japanese routine clinical practice.

Safety of Conversion From Twice-Daily Tacrolimus (Prograf) to Once-Daily Prolonged-Release Tacrolimus (Advagraf) in Stable Liver Transplant Recipients

Nonadherence to immunosuppressive regimens among solid organ transplantation to range has been estimated from 15% to 55%. This problem has been identified as a leading cause of preventable graft loss. Tacrolimus once daily Advagraf has been developed to provide a more convenient dosing regimen to improve adherence. The aim of this study was to analyze the safety of a 1:1 dose conversion from twice-daily tacrolimus (Prograf) to Advagraf in 36 stable liver transplant recipients. The tacrolimus whole blood trough level at T0 was 6.7 ± 2.9 ng/mL with a daily dose of 3.7 ± 1.8 mg. The mean tacrolimus blood trough levels at T1 (7 days) and T2 (14 days) were 5.8 ± 2.5 and 5.8 ± 1.8 ng/mL with mean daily doses of 3.9 ± 1.9 and 4.1 ± 1.8 mg, respectively. There was no significant difference between T0, T1, and T2, either for tacrolimus blood trough levels or for tacrolimus daily dosages. Liver and renal function tests remained stable; no episodes of acute rejection were encountered after the conversion. A switching policy using a dose ratio of 1:1 from twice-daily tacrolimus to once-daily prolonged-release tacrolimus was safely applied to stable liver transplant recipients.     

Prolonged-Release vs Immediate-Release Tacrolimus Capsules in Black vs White Kidney Transplant Patients: A Post Hoc Analysis of Phase III Data

Background

Black kidney transplant patients experience inferior outcomes compared with other ethnicities. Because scrutiny is required when immunosuppressant drugs are used in such at-risk populations, we report the first large-scale clinical efficacy data assessing prolonged-release tacrolimus (PR-T) in black de novo kidney transplant patients.

Conversion From Twice-Daily to Once-Daily Tacrolimus in Simultaneous Pancreas-Kidney Transplant Patients

Background

Data on the effectiveness of once-daily tacrolimus (Tac-QD) in simultaneous pancreas-kidney (SPK) transplant patients are limited, which is of particular concern because diabetic gastroparesis may affect absorption. The aim of this study was to evaluate the clinical impact of converting SPK patients from twice-daily (Tac-BD) to Tac-QD.

Methods

From November 2008 to August 2011, 27 SPK recipients (out of 130) were converted from Tac-BD to Tac-QD. Demographics, prescribed doses, trough levels, and creatinine, glucose, and Hb_A1c values were collected prospectively at the time of conversion and at 1, 2, 3, 6, and 12 months after conversion.

Results

The mean time from transplantation to conversion was 35.81 ± 27.31 months, with 20 patients (74.07%) converted to Tac-QD >12 months after transplantation. There were no significant differences in the tacrolimus dose and trough levels before and after conversion and at all points during the follow-up. Creatinine, glucos,e and Hb_A1c levels remained stable throughout. Eight patients (29.63%) with gastroparesis had clinical outcomes, drug doses, and trough levels similar to all other patients.

Conclusions

Stable SPK recipients can safely be converted from Tac-BD to Tac-QD, with no clinical impact on the transplant function. Gastroparesis does not appear to influence tacrolimus dose requirements or trough levels.     

Effects of Conversion From a Twice-Daily Tacrolimus to a Once-Daily Tacrolimus on Glucose Metabolism in Stable Kidney Transplant Recipients

Introduction

The adverse effects of tacrolimus are known to play major roles in new-onset diabetes after transplantation. The purpose of this study was to investigate the effects of conversion from a twice-daily tacrolimus (Tac-BID) to a once-daily tacrolimus (Tac-OD) on glucose metabolism in stable kidney transplant recipients.

Patients and methods

Twenty-six patients were converted from Tac-BID to Tac-OD on a 1:1 mg basis and examined for its effects on glucose metabolism. Unless rejection or tacrolimus toxicity was suspected, we did not perform dose adjustments of Tac-OD or reconversion to Tac-BID until 4 weeks after conversion. Subsequent dose adjustments were allowed to maintain tacrolimus target trough concentration within the. Changes in clinical parameters were compared between baseline and 24 weeks after conversion.

Results

Conversion from Tac-BID to Tac-OD on a 1:1 mg basis resulted in a significant decrease in tacrolimus trough level at 4 weeks after conversion. Because dose adjustments were performed, the trough level did not differ significantly between baseline and 24 weeks after conversion. At 4 and 24 weeks after conversion, the homeostasis model assessment of pancreas β-cell function (HOMA-β) increased significantly.

Conclusions

Although there was no change in tacrolimus trough level between baseline and 24 weeks after transplantation, HOMA-β at 24 weeks after conversion was significantly higher than that at baseline. These results indicated that conversion from Tac-BID to Tac-OD may improve pancreas β-cell function in kidney transplant recipients.     

Conversion From Calcineurin Inhibitors to Sirolimus in Kidney Transplant Recipients: A Retrospective Cohort Study

Background

Replacing a calcineurin inhibitor (CNI) with sirolimus (SRL) may preserve kidney graft function. However, at the present time, only short follow-up after conversion is available. The aim of this study was to assess whether conversion from a CNI-based to an SRL-based maintenance regimen was safe and effective.

Materials and methods

We performed a retrospective cohort study among kidney graft patients whose CNI was withdrawn to be replaced by SRL. Two-tailed paired t tests were used to compare glomerular filtration rates (GFRs) and proteinuria levels before and up to 2 years after conversion. We used linear regression to determine the factors associated with changes in renal function after conversion.

Results

The 193 study subjects had a mean GFR at conversion of 41 ± 16 mL/min/1.73 m² a median proteinuria level of 0 g/L (interquartile range = 0-0.15). After conversion, the GFR was stable: at 1 year, the change was −0.34 mL/min/1.73 m² (95% confidence interval [CI] = −2.71, 2.03) and at 2 years, −0.96 mL/min/1.73 m² (95% CI = 4.26, 2.34). There was a small but significant increase in dipstick proteinuria at 1 year of +0.5 g/L, (95% CI = 0.20, 0.75). On multivariate analysis, proteinuria ≥ 1 g/L at the time of conversion was the only predictor of deteriorating GFR at 1 year (β: −7.91 mL/min/1.73 m²; 95% CI = −14.10, −1.70). SRL had to be discontinued in 31% of patients.

Conclusion

Conversion from CNI to SRL resulted in stable graft function at 2 years and in a slight increase in proteinuria. Despite the relatively high reconversion rate, this strategy offers a reasonable alternative to CNIs for most patients.     

Conversion From Twice-Daily to Once-Daily Tacrolimus Administration in Liver Transplant Patient

Background

Compliance to immunosuppressive therapy is critical to prevent organ rejection and possible graft loss. A once-daily Tacrolimus formulation that may improve adherence-to-therapy while allowing the same patient care strategies, total daily dose and monitoring techniques that have been recently approved. The present study was sought to evaluate the feasibility of this formulation among liver transplantation patients (OLT).

Materials and Methods

Patients transplanted for at least 6 months were enrolled if they had stable doses of Tacrolimus over the last 3 months. Conversion from a twice to a once-daily regimen was based on a 1 mg:1 mg proportion. Tacrolimus blood levels were assessed at 0, 15, 30, 60, 90 days as well and 6 months after conversion. We recorded liver and renal function as well as adverse events.

Results

Among twenty-eight patients enrolled in the study including 23 males and 5 females the overall mean age was 59 ± 8 years and the mean distance from OLT was 39 ± 22. 32% of patients did not require any dose adjustment. In contrast, 43% required an increase (+0.6 ± 0.3 mg/d), while 25%, a decrease (−0.5 ± 0.0 mg/d) in the drug dose to maintain the same tacrolimus blood concentrations as at baseline. Ninety percent of patients stabilized blood levels within 45 days. None of the patients experienced adverse events or alterations in liver function.

Conclusions

Our study confirmed that once-daily Tacrolimus is a useful therapeutic option for OLT patients; however dose adjustments are frequently needed in the short term. The drug is safe and may improve patient compliance.     

Efficacy and Safety Evaluation After Conversion From Twice-Daily to Once-Daily Tacrolimus in Stable Liver Transplant Recipients: A Phase 4, Open-Label,Single-Center Study

BackgroundSimplifying immunosuppressive therapy after liver transplant may improve patient compliance, thereby preventing acute rejection and graft loss. This phase 4, open-label, single-center study was conducted to evaluate the efficacy and safety of twice-daily to once-daily tacrolimus conversion in stable liver transplant recipients.MethodsBetween May 2017 and January 2019, twice-daily tacrolimus was converted to once-daily tacrolimus in 101 stable recipients at least 12 months post-liver transplant in Asan Medical Center. The doses of both drugs was converted to 1:1, and the target trough level was 5 to 10 ng/mL. We prospectively analyzed graft function, drug compliance, and adverse reactions after switching regimen for 24 weeks.ResultsThere was no acute rejection confirmed histologically within 24 weeks, which was the primary endpoint, and there was no chronic rejection, fatal deterioration of liver function, or death in any patient during this period. After conversion, the trough level of tacrolimus decreased, and the mean ± standard deviation differences between the trough level and baseline level were 1.46 (±2.41) ng/mL, 0.43 (±2.08) ng/mL, and 0.07 (±2.73) ng/mL at 3, 12, and 24 weeks after conversion, respectively. Despite transient fluctuations of the trough level, there was no evidence of rejection or graft dysfunction. There were 37 adverse reactions after conversion; most of them were mild, and thrombocytopenia developed in 1 patient as an adverse drug response. Drug compliance improved after conversion according to questionnaire responses.ConclusionsThe conversion to once-daily tacrolimus in stable liver transplant recipients is an effective and safe therapeutic strategy improving drug compliance.     

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

Bioequivalence of the recently available generic tacrolimus formulation, manufactured by Sandoz, to the reference product (Prograf; Astellas Pharma, Tokyo, Japan) has been demonstrated in healthy subjects. However, the safety and efficacy of substitution with generic tacrolimus in transplant patients have not been evaluated. Tacrolimus trough concentrations and indices of liver and kidney function were recorded before and after generic substitution in 48 liver and 55 kidney transplant recipients. In liver transplant patients, the mean tacrolimus concentration/dose (C/D) ratio (±SD) was 184.1 (±123.2) ([ng/mL]/[mg/kg/day]) for the reference product and 154.7 (±87.8) ([ng/mL]/[mg/kg/day]) for the generic product (p < 0.05). The mean C/D‐ratios in kidney transplant patients were 125.3 (±92.7) and 110.4 (±79.2) ([ng/mL]/[mg/kg/day]) for the reference and generic products, respectively (p < 0.05). Actual trough concentrations declined by an average of 1.98 ng/mL in liver and 0.87 ng/mL in kidney transplant patients following the switch, after accounting for all significant covariates. No change was observed in biochemical indices of liver or kidney function and no cases of acute rejection occurred following the substitution. These results suggest that transplant patients currently taking the reference tacrolimus formulation may be safely switched to the Sandoz‐generic product provided trough concentrations are closely monitored following the substitution.     

Impact of Conversion From Cyclosporine to Tacrolimus on Glucose Metabolism and Cardiovascular Risk Profiles in Long-Term Stable Kidney Transplant Recipients

BackgroundCompared to tacrolimus, cyclosporine increases cardiovascular risk. Furthermore, tacrolimus has a negative effect on glucose metabolism compared to cyclosporine. This study investigated the effect of the conversion from cyclosporine to tacrolimus for immunosuppressive therapy on glucose metabolism and cardiovascular risk profiles in long-term stable kidney transplant recipients (KTRs).MethodsIn this prospective, open-label, single-arm study, 36 KTRs were enrolled; 3 were excluded. Patients were evaluated for glucose metabolism and cardiovascular risk factors at baseline, 3, and 6 months after conversion of medication. Serial changes were analyzed by repeated analysis of variance.ResultsThe mean duration from transplantation was 12.6 ± 4.0 years and baseline serum creatinine levels were 1.10 ± .23 mg/dL. After conversion, fasting plasma glucose levels increased sequentially from 101.7 ± 18.5 to 107.4 ± 21.3 mg/dL (P = .007), and glycated hemoglobin levels increased from 5.7 ± .8 to 6.0 ± 1.2% (P = .016). Among cardiovascular risk factors, fibrinogen levels were decreased (P = .015), but other factors, including blood pressure and lipid profile, did not change (all P > .05). There was no change in renal function, including serum creatinine (P = .611) and urine protein-to-creatinine ratio (P = .092). Body mass index levels were decreased (P = .037) and body weight tended to decrease (P = .063).ConclusionsSwitching immunosuppressant therapy to tacrolimus has an apparent negative effect on glucose metabolism and imparts an unclear advantage on cardiovascular risk profiles for long-term stable KTRs.     

Conversion of Twice‐Daily Tacrolimus to Once‐Daily Tacrolimus Formulation in Stable Pediatric Kidney Transplant Recipients: Pharmacokinetics and Efficacy

The pharmacokinetics, efficacy and safety of once‐daily tacrolimus formulation (Tac‐OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice‐daily tacrolimus formulation (Tac‐BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac‐OD on a 1:1 basis and maintained on a once‐daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C₀ concentrations (4.10 ± 1.16–3.53 ± 1.10 ng/mL, p = 0.004), and AUC_0–24 (151.8 ± 41.6–129.8 ± 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac‐OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac‐BID can be safely converted to Tac‐OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated.

     

Safe Conversion From Tacrolimus to Belatacept in High Immunologic Risk Kidney Transplant Recipients With Allograft Dysfunction

There is no literature on the use of belatacept for sensitized patients or regrafts in kidney transplantation. We present our initial experience in high immunologic risk kidney transplant recipients who were converted from tacrolimus to belatacept for presumed acute calcineurin inhibitor (CNI) toxicity and/or interstitial fibrosis/tubular atrophy. Six (mean age = 40 years) patients were switched from tacrolimus to belatacept at a median of 4 months posttransplant. Renal function improved significantly from a peak mean estimated glomerular filtration rate (eGFR) of 23.8 ± 12.9 mL/min/1.73 m² prior to the switch to an eGFR of 42 ± 12.5 mL/min/1.73 m² (p = 0.03) at a mean follow‐up of 16.5 months postconversion. No new rejection episodes were diagnosed despite a prior history of rejection in 2/6 (33%) patients. Surveillance biopsies performed in 5/6 patients did not show subclinical rejection. No development of donor‐specific antibodies (DSA) was noted. In this preliminary investigation, we report improved kidney function without a concurrent increase in risk of rejection and DSA in six sensitized patients converted from tacrolimus to belatacept. Improvement in renal function was noted even in patients with chronic allograft fibrosis without evidence of acute CNI toxicity. Further studies with protocol biopsies are needed to ensure safety and wider applicability of this approach.     

Impact of Clotrimazole Fungal Prophylaxis on Tacrolimus Exposure in Kidney Transplant Recipients: A Retrospective Study

Tacrolimus, an immunosuppressant prescribed to reduce the risk of organ rejection, is metabolized by cytochrome P450 and is a substrate for P-glycoprotein. Many medications affect tacrolimus concentrations, making it difficult to maintain exposure within its narrow therapeutic index. Clotrimazole troches, prescribed to posttransplant recipients immediately for the first 30 days for oral candidiasis prevention, are considered nonsystemic. However, data suggest a potential drug interaction, affecting tacrolimus exposure. To assess the magnitude of the effect of clotrimazole on tacrolimus trough levels, 97 kidney transplant recipients, on a stable dose of tacrolimus, were retrospectively evaluated. Tacrolimus trough concentrations were analyzed 7 and 14 days before and after discontinuation of clotrimazole. The median change in tacrolimus trough level was ?1.3 ng/mL (confidence interval, ?2.5, ?1.0; P < .001) at day 7 and ?2.8 ng/mL (confidence interval, ?3.3, ?1.6; P < .001) at day 14 after clotrimazole discontinuation, from a median baseline of 8.9 ng/mL. Overall, a reduction in tacrolimus level was observed in 60% of patients after discontinuation of clotrimazole. When assessing the effect of race and sex, no influence was found on the degree of change in tacrolimus level after clotrimazole discontinuation. In conclusion, clotrimazole exerts a significant interaction on tacrolimus where close monitoring of tacrolimus trough levels after discontinuation of clotrimazole is warranted.     

Conversion of Stable Kidney Transplant Recipients From a Twice-Daily to Once-Daily Everolimus Regimen

Once-daily everolimus administration is a further option to improve compliance to immunosuppressive therapy. We randomized 23 stable kidney transplant recipients already on everolimus therapy to receive a single daily morning dose or to continue the twice-daily regimen. The everolimus levels evaluated after 2 weeks showed a slight reduction from 5.13 ± 1.61 ng/mL at baseline to 4.76 ± 1.61 ng/mL, which was not statistically significant. After 2 weeks we also evaluated cyclosporine (CsA) levels together with renal function parameters, neither of which showed episodes, any difference between the converted versus twice-daily groups. We did not record any adverse event, such as an infection, an acute rejection episode, or graft loss, over the 6-month study period. Single dosing of everolimus is possible and safe and may achieve better patient compliance to multiple-drug immunosuppressive therapy.     

Monotherapy With Tacrolimus for Heart and Liver Transplant: A Case Report

Background

Multiple-organ transplantation cases are rare, partly due to the shortage of donor organs. However, recent reports of outcomes of multiple-organ transplantations show encouraging survival rates for recipients as compared to single-organ transplant recipients.

Case report

A 33-year-old female who was a known hepatitis B carrier and who had been diagnosed with peripartum dilated cardiomyopathy was experiencing end-stage heart failure. The patient received orthotopic heart transplantation. After heart transplantation, the recipient received prednisolone, cyclosporine, and mycophenolate mofetil for immunosuppressive therapy. Seventy-one days later, the recipient began to develop progressive jaundice, ascites, and hepatoencephalopathy and was re-admitted to the hospital. Fulminant hepatitis was diagnosed. She was referred for emergency cadaveric liver transplantation 110 days after the heart transplantation because of her critical condition. After transplantation, she was improved and her condition maintained by a single immunosuppressive therapy, tacrolimus, with mean dose of 0.06 mg/kg/d.

Conclusion

We presented a case that was complicated by fulminant hepatitis after heart transplantation and successfully rescued by liver transplantation.