Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen

Modified release (MR) tacrolimus is an extended release formulation administered once daily (qD). The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable kidney transplant recipients converted from Prograf twice a day to MR tacrolimus qD. METHODS: This was an open-label, multicenter study with a crossover design. Eligible patients were 18 to 65 years of age, more than 6 months posttransplant with stable renal function, and received stable Prograf doses more than 2 weeks prior to enrollment. Patients received Prograf twice a day through day 7; 24-hour PK profiles were obtained on days 1 and 7. Patients were converted to the same milligram-for-milligram daily dose of MR tacrolimus qD in the morning on day 8; 24-hour PK profiles were obtained for MR tacrolimus on days 8, 14, and 21. Laboratory and safety parameters were also evaluated. RESULTS: Most patients (67 of 70) completed all 5 PK profiles. The 90% confidence intervals (CI) for the MR tacrolimus vs Prograf comparison at steady state (days 14 and 21 vs days 1 and 7) were 90.7 and 99.4 for AUC0-24 and 82.7 and 91.9 for Cmin. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 1, r = 0.80; day 7, r = 0.84) and MR tacrolimus (day 14, r = 0.92; day 21, r = 0.86). Renal function remained stable after conversion to MR tacrolimus. CONCLUSION: The steady state PK of MR tacrolimus are equivalent to Prograf after a milligram-for-milligram conversion in stable kidney transplant recipients. The results provide evidence to support a safe 1:1 conversion from Prograf twice a day to MR tacrolimus.     

Improved kidney graft function after conversion from twice daily tacrolimus to a once daily prolonged-release formulation

Background

Tacrolimus once daily (Tac-QD) formulation has been recently introduced to improve patient adherence to immunosuppressive medications. To evaluate long-term effects of conversion from tacrolimus twice daily (Tac-BID) to Tac-QD on kidney graft excretory function, we retrospectively analyzed kidney graft function after the conversion from Tac-BID to Tac-QD over 24 months.

Methods

We enrolled 72 kidney transplant recipients, including 19 simultaneous pancreas-kidney cases, who were at least 9 months posttransplantation and showed stable graft function for 6 months. We analyzed kidney graft function (glomerular filtration rate [eGFR] by the Modification of Diet in Renal of Disease equation), tacrolimus daily dose and tacrolimus blood trough level changes over 24 months after conversion.

Results

All patients completed the 12 months and 56 patients, 24 months observation. At 3 months, the eGFR increased significantly after conversion from 57.1 to 60.0 mL/min/1.73 m² (P = .004) and at 24 months to 66.0 mL/min/1.73 m² (P < .001). Tacrolimus daily dose diminished over time by almost 10%, a difference that reached statistical significance at 18 months. Tacrolimus blood trough levels did not change significantly until 24 months. There was no correlation between eGFR changes during the first 12 months after conversion and changes in tacrolimus blood trough levels (r = −0.118; P = .33).

Conclusion

Conversion from Tac-BID to Tac-QD formulation was followed by a clinically significant improvement in kidney graft function upon long-term observation. The improvement seemed to not be related to changes in tacrolimus blood trough levels.     

Significant reduction of Tacrolimus trough level after conversion from twice daily Prograf to once daily Advagraf in Chinese renal transplant recipients with or without concomitant diltiazem treatment

Abstract

A dose ratio of 1:1 was recommended for the conversion from Standard-release Tacrolimus (Prograf) to Prolonged-release Tacrolimus (Advagraf). We investigated the trough tacrolimus blood level in Chinese kidney transplant recipients after conversion, including subjects receiving concomitant treatment with diltiazem. Eighteen stable renal allograft recipients were followed prospectively for 12 weeks after conversion from Prograf to Advagraf at the same daily dose. Tacrolimus blood trough level decreased significantly within 8 weeks after conversion (p?<?0.01). Twelve patients required escalation of the Advagraf dose by 1.10?±?0.36?mg. For the whole group the daily tacrolimus dose was increased from 0.057?±?0.032?mg/kg to 0.068?±?0.033?mg/kg (p?<?0.0001). At week 12 the daily dose of Advagraf was 127?±?32% of the original daily dose of Prograf. In the subgroup of patients receiving diltiazem, their tacrolimus trough level decreased significantly after conversion (p?=?0.001), and the daily tacrolimus dose was increased from 0.060?±?0.036?mg/kg to 0.073?±?0.036?mg/kg (p?<?0.0001). At week 12, their daily dose of Advagraf was 131?±?34% of the original daily dose before conversion. To conclude, conversion from Prograf to Advagraf in renal allograft recipients with or without diltiazem co-treatment necessitated an increase in the daily dose by approximately 30% to maintain the target blood trough level unchanged.     

Improvement of graft function after conversion to once daily tacrolimus of stable kidney transplant patients

Background

Chronic renal dysfunction is present in about one quarter of kidney transplant patients at 1 year and in about 90% by 10 years. Nephrotoxicity caused by calcineurin inhibitors is among the most common factors. Elevated tacrolimus levels have been correlated with worse control of side effects including acute and/or chronic nephrotoxicity. The aim of this study was to observe the effects on graft function of conversion from the twice daily to the once daily extended release tacrolimus formulation in stable kidney transplant recipients within 5 years of grafting.

Methods

Thirty-one stable kidney transplant patients were converted at the same dosage (1 mg:1 mg). Patients served as their own controls based on results before versus after conversion.

Results

The trough levels of tacrolimus showed a slight albeit significant reduction after the conversion. Serum creatinine and glomerular filtration rate showed a significant improvement without an association with the tacrolimus trough levels.

Conclusion

We suggest that the immunosuppression with once daily tacrolimus may be a good option for kidney transplant patients.     

Tacrolimus conversion in kidney transplant recipients: analysis of 107 patients

Early results of an alteration in immunosuppressive protocol of tacrolimus conversion at a mean follow-up of 16 (range 1 to 36) months are presented with a mean time after transplantation of 34 +/- 1.4 months (range 1 to 158 months). Chronic allograft nephropathy in 16 (17%) patients, nephrotoxicity related to cyclosporine in 27(23%) patients and steroids resistant acute rejection in 64 (58%) represented the indications for tacrolimus conversion. Before starting tacrolimus there were 1 acute rejection episode in 37 patients, 2 in 17 patients, and 3 in 10 patients. After the drug conversion, 1 acute rejection occurred in 18 and 2 acute rejection in 4 patients. Graft loss was seen in 16 (16%) patients after drug conversion. Tacrolimus was withdrawn due to diabetes mellitus (n = 9), epilepsy (n = 4), and severe Nocardia sepsis, lymphoma and Kaposi sarcoma (each in one patient). Decreases in serum creatinine and increases in blood glucose levels were significantly associated with the tacrolimus doses (P = 0.0004 and P = 0.0400, respectively). The increase in creatinine clearance values were closely related to higher tacrolimus levels. The target range with maximum efficacy and minimum toxicity seemed to be 10 to 15 ng/mL. Tacrolimus conversion can be successful in cases of rejection and nephrotoxicity, but dose-dependent blood glucose elevations require close observation in these patients.     

Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients

BACKGROUND: There is limited data on the potential nephrotoxicity of sirolimus (SRL) and tacrolimus (TAC) in combination. METHODS: We reviewed the course of 97 kidney transplant patients treated with SRL and reduced-dose TAC. Conversion from SRL to mycophenolate mofetil (MMF) was prescribed in a minority (n = 19) for various nonrenal side effects. We compared outcomes of converted patients to those remaining on TAC/SRL (n = 78). RESULTS: TAC levels were increased in converters (P = 0.009). Rejection rates were similar between groups over 18 months (21% vs. 16%, p = ns). Serum creatinine (Cr) and MDRD glomerular filtration rate (GFR) were similar between groups at nadir and six-months, but at 18 months the percent change from six-month Cr was +17% in non-converters vs. -10% in converters (P = 0.004 for the difference). The difference in GFR between groups at 18 months was also significant (P = 0.01). By multivariate analysis, only conversion to MMF was associated with a greater percent change in Cr from 6 to 18 months (P = 0.015). Conversion to MMF also correlated with higher GFR at 18 months independent of rejection, delayed graft function, and ethnicity. CONCLUSIONS: Conversion from TAC/SRL to TAC/MMF led to improved renal function despite increased TAC exposure after conversion.     

Conversion from cyclosporine to tacrolimus in pediatric kidney transplant recipients

In pediatric kidney transplant recipients, tacrolimus has been proposed either for primary immunosuppression or as a rescue agent for refractory acute rejection, chronic rejection, and cyclosporine toxicity. This paper describes our experience with tacrolimus conversion from cyclosporine-based therapy in six selected cases: four due to refractory acute rejections unresponsive to conventional therapy, one to chronic graft rejection, and one to cyclosporine-related hypertrichosis. A "simple-switch" conversion was used without any overlap, starting with a dose of 0.2 mg/kg per day. The time to conversion varied from 10 to 730 days after the transplant. In the patients with acute rejection, the median time to reversal after tacrolimus conversion was 12 days. The symptoms of the patient with cyclosporine toxicity completely resolved without any loss of allograft function. The patient with chronic rejection maintained stable renal function for more than 1 year after conversion. A new onset of post-transplant diabetes mellitus and dose-related nephrotoxicity were recorded as adverse events. In conclusion, our experience suggests that tacrolimus can play an important role in the salvage treatment of pediatric kidney transplantations with deteriorating graft function due to acute rejection refractory to standard therapy. Tacrolimus conversion also provides excellent results in the presence of cyclosporine toxicity.     

Effect of conversion from twice-daily to once-daily tacrolimus on glucose intolerance in stable kidney transplant recipients

Background

Tacrolimus is an established immunosuppressant for the prevention and treatment of allograft rejection in organ transplantation. However, tacrolimus therapy also has several adverse effects. The main aim of this study was to evaluate the effect of conversion from twice-daily tacrolimus (tacrolimus-BID) to once-daily tacrolimus (tacrolimus-OD) on glucose intolerance in stable kidney transplant patients.

Methods

The study comprised 43 kidney transplant recipients with stable renal function. The same 1 mg:1 mg dose conversion was used for all patients. Follow-up, which included clinical evaluation and laboratory testing, was performed at 30, 60, and 120 days after conversion. The parameters for which the baseline and end-point values were determined included homeostasis model assessment of beta-cell function (HOMA-B) scores, hemoglobin A_1c (HbA_1c) levels, serum insulin levels, and fasting glucose levels.

Results

The tacrolimus trough levels did not differ significantly at 120 days after conversion. There was a significant increase in serum insulin level at 120 days after conversion (baseline, 5.6 ± 2.7 μU/mL; end point, 6.6 ± 3.4 μU/mL; P < .009). The HOMA-B score slightly increased (baseline, 58.7 ± 33.1; end point, 65.6 ± 32.8; P = .091) at 120 days after conversion, indicating beta-cell function. Serum creatinine concentration, blood glucose level, and HbA_1c level did not change significantly during follow-up examinations. Episodes of acute rejection or graft loss did not occur.

Conclusion

The results of this study suggests that conversion from tacrolimus-BID to tacrolimus-OD may benefit kidney transplant patients with glucose intolerance because of improved insulin secretion. Further studies involving a larger sample population and longer follow-up time are required to verify the results of this study.     

肾移植患者他克莫司血药浓度与肝肾毒性分析

目的分析我院肾移植患者他克莫司血药浓度的控制情况,探讨他克莫司血药浓度与肝肾功能之间的关系,以期为临床的合理用药提供依据。方法收集我院2011年11月至2013年4月96例肾移植患者他克莫司血药浓度的数据,及血药浓度测定当天的生化检测结果。根据他克莫司血药浓度（A）测定结果,将其分为4组（I组,A≤6 ng/mL;II组,6〈A≤10 ng/mL;III组,10〈A≤15 ng/mL;IV组,A〉15 ng/mL）,对4组中的各项生化指标及不良反应比例进行统计分析。结果红细胞（P=0.57）,血红蛋白（P=0.60）,血小板（P=0.12）,总胆红素（P=0.58）,谷氨酰基转移酶（P=0.46）,天门冬氨酸氨基转移酶（P=0.98）和丙氨酸氨基转移酶（P=0.40）在4组之间没有统计学意义;而白细胞（P=0.007）,碱性磷酸酶（P=0.004）和血尿素氮（P=0.007）在4组之间差异有统计学意义。当患者的他克莫司血药浓度维持在6-15 ng/mL 时,其肾小球滤过率估计值（estimated glo-merular filtration rate,eGFR）（70.2 mL/min）要明显高于≤6 ng/mL（58.2 mL/min）和〉15 ng/mL （66.2 mL/min）。同时,感染及中重度贫血的风险也较低,但他克莫司血药浓度与肝功能异常比例之间未发现显著的相关性。结论他克莫司血药浓度维持在6-15 ng/mL有利于患者肾功能的维持,同时能够降低感染和中重度贫血的风险,这一结果将有利于他克莫司的临床使用。     

Two cases of severe de novo colitis in kidney transplant recipients after conversion to prolonged‐release tacrolimus

Diarrhea is a frequent complication in patients after solid organ transplantation. We describe two cases of severe new onset colitis in kidney transplant recipients that developed shortly after the introduction of the therapy with prolonged‐release formulation of tacrolimus replacing standard twice daily formulation of tacrolimus in one case and cyclosporine A in the second case. Both patients developed severe, intermittent bloody diarrhea with abdominal pain, weight loss, dehydration and worsening graft function that required immediate hospitalization. The symptoms did not diminish after dose reduction or withdrawal of mycophenolic acid derivatives. After excluding bacterial, viral, fungal, and parasite infections, colonoscopy with colonic biopsy was performed in both patients, which revealed features typical of colitis. Both patients received mesalazine until the symptoms stopped. In one of the patients, standard formulation of tacrolimus was immediately reintroduced. The second patient was given everolimus in an acute phase of diarrhea. Although the two cases presented in this report cannot fully support a causal relationship between the prolonged‐release tacrolimus and colitis, they should increase awareness among transplant physicians and prompt more close monitoring of such potential side effects as a part of the pharmacovigilance plan for a new formulation of the well‐established immunosuppressive drug.     

稳定期肾移植受者将他克莫司普通剂型转换为缓释剂型对移植肾功能的影响

目的观察稳定期肾移植受者由普通剂型他克莫司(Tac)转换为缓释剂型Tac后对移植肾功能的影响。方法回顾性分析山西省第二人民医院2011年12月至2019年6月由普通剂型Tac转换为缓释剂型Tac的83例稳定期肾移植受者,随访12~36个月,同时匹配83例继续服用普通剂型Tac的稳定期肾移植受者作为对照组。观察稳定期肾移植受者由普通剂型Tac转换为缓释剂型Tac后肾功能、谷值浓度个体内变异度(IPV)及依从性的变化、排斥反应的发生率及移植肾和移植受者的存活率。结果普通剂型Tac转换为缓释剂型Tac时间为移植后(42.76±30.50)个月,转换后24个月血清肌酐(SCr)明显低于转换前(P=0.013),估算肾小球滤过率(eGFR)明显高于转换前(P=0.005)。试验组较对照组在转换后36个月SCr明显降低(P=0.017),eGFR明显增高(P=0.038)。试验组转换前免疫抑制剂治疗障碍量表(ITBS)得分为(20.23±2.89)分,转换后为(17.63±3.08)分(P=0.000);Tac每日剂量转换前是(2.09±0.84)mg,转换后为(2.10±0.83)mg;Tac谷值浓度转换前为(7.22±2.84)ng/mL,转换后显著降低,人/肾均健康存活。结论稳定期肾移植受者由普通剂型Tac转换为缓释剂型Tac肾功能保持稳定且较普通剂型Tac相对更好,依从性明显改善,谷值浓度个体内变异度明显降低,长期服用的临床疗效和安全性良好。     

Increased adherence after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation: a pre-experimental study

Background

Modified release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. Simplification of regimen has been associated with better adherence. This study evaluated patient adherence, as well as safety and efficacy among chronic stable heart transplantation (HT) patients switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to (once daily) modified release TAC.

Methods

We switched 54 chronic stable patients (41 males and 13 females) from twice daily dosing with conventional TAC or CsA to once daily dosing with modified release TAC. Self-reported adherence was assessed at baseline and at 4 months after the switch using the Basel Assessment of Adherence with Immunosuppressive Medication Scale [BAASIS]), a 4-item validated questionnaire including also a Visual Analogue Scale (VAS). Nonadherence was defined as any self-reported nonadherence on any item.

Results

Modified release TAC was discontinued in 4 patients because of diarrhea (n = 1) or gastrointestinal discomfort (n = 3) leaving 50 evaluable patients. Overall nonadherence at baseline for any of the 4 items was 74% versus 38% after 4 months (P = .0001). Thereafter, adherence improved in 28 patients (56.0%), was unchanged in 18 (36.0%), and decreased in 4 subjects (8.0%). The VAS score improved from 82.3% ± 2.6% to 97.5% ± 4.8% (P < .0001). No significant changes were observed after 4 months regarding hematologic, renal, or liver function parameters (all P = NS).

Conclusions

Therapeutic regimens for transplant recipients are often complex, contributing to a high incidence of medication nonadherence. This study in chronic, stable, heart transplantation patients demonstrated a significant improvement in patient adherence after a switch to modified release TAC, which was generally well tolerated.     

Predictors of renal function improvement following tacrolimus conversion in cyclosporine-treated kidney transplant recipients

The objective of this study was to evaluate the relationship between variability of cyclosporine (CsA) absorption and tacrolimus (TAC) conversion seeking factors that predict improvement in allograft function after TAC conversion. We performed a retrospective study of 44 adult kidney transplant recipients undergoing conversion from CsA to TAC-based immunosuppression. Before TAC conversion, patients had complete, consecutive, 6 monthly C2 levels and a follow-up duration beyond 6 months after TAC conversion. The patients were divided into 2 groups: one (n=23) with low variability of CsA absorption and one (n=21) with high variability of CsA absorption. At TAC conversion, the estimated glomerular filtration rate (eGFR) was similar in both patient groups. Six months after TAC conversion, eGFR improved in both groups. Stepwise regression analysis revealed the DeltaSCr6 (change in serum creatinine level at 6 months) to be independently associated with the preconversion serum creatinine (SCr; P<.0001) and the percent coefficient of variation (%CV) of SCr (P=.0034). DeltaSCr6 was inversely associated with posttransplantation years (P=.0033), and 6-month TAC blood levels (P=.0053). The DeltaSCr6 was not associated with variability of oral CsA absorption. The cutoff value of baseline SCr at TAC conversion differentiated an increase in or reduction of SCr to be about 1.0 mg/dL. Our study of CsA-treated kidney transplant recipients who underwent TAC conversion showed that a preconversion SCr>1.0 mg/dL, a high variability of SCr, and early TAC conversion predicted greater short-term benefit on graft function.     

A switch from conventional twice-daily tacrolimus to once-daily extended-release tacrolimus in stable kidney transplant recipients

Background

Extended-release tacrolimus (TAC-ER) was developed to provide a more convenient treatment compliance and improve safety by avoiding toxic peak levels. We prospectively evaluated the safety and effectiveness of a 1:1 dose switch from twice-daily tacrolimus to once-daily TAC-ER in stable kidney transplant recipients and assessed their satisfaction with the regimen.

Patients and methods

Tacrolimus was switched to TAC-ER (1:1 dose) in 12 kidney transplant recipients with stable renal function from March 2010 to August 2011. The posttransplantation follow-up period was 7.6 ± 4.3 years (range 1.5-13.2 years). No patient had diabetes mellitus in this group. We evaluated the tacrolimus trough levels, serum creatinine, potassium, glucose, glycohemoglobin (HbA1c), and urine protein concentrations once a month from 6 months prior to 1 year after switching. A satisfaction survey for TAC-ER treatment was performed 3 months after the switch. The questionnaire included administration compliance questions such as “forget to take less often,” “easy to carry,” “easy to store,” and “general satisfaction.”

Results

After the switch to TAC-ER, we observed a quick and sustained 25% decrease in TAC trough levels from 4.8 ± 1.0 to 3.6 ± 0.8 (P = .0002). No significant differences in serum creatinine, potassium, glucose, HbA1c, or urine protein concentration were observed during the 14.6 ± 2.6 months' follow-up period. No recipient experienced acute rejection. The satisfaction survey demonstrated that the stable kidney transplant recipients were satisfied with the switch.

Conclusions

A switch from twice-daily tacrolimus to once-daily TAC-ER (1:1 dose) was safe and effective. TAC-ER can improve treatment compliance in stable kidney transplant recipients.     

Safety and efficacy of conversion from twice-daily tacrolimus (prograf) to once-daily prolonged-release tacrolimus (graceptor) in stable kidney transplant recipients

Background

Graceptor is a new modified-release once-daily formulation of tacrolimus with an efficacy and safety profile similar to twice-daily tacrolimus (Prograf), as identified by clinical trials, offering 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 Prograf to once-daily Graceptor in stable kidney transplant recipients.

Methods

We switched 33 Japanese patients who had undergone kidney transplantation ≥1 years before from twice-daily Prograf to once-daily Graceptor. The dose conversion ratio between Prograf and Graceptor was 1:1. We compared the following parameters: minimum tacrolimus concentration (C_min); concentration dose per weight (CDW); serum creatinine (sCr); blood urea nitrogen (BUN); total cholesterol (TC); high-density lipoprotein cholesterol (HDL-C); uric acid (UA); fasting blood sugar (FBS). Time points for measurements were 1 month before study start and 1 and 2 months afterward.

Results

The mean age of the subjects in this study was 46.5 ± 13.1 years. Mean C_min decreased from 4.55 ± 1.79 to 3.20 ± 1.22 ng/dL. The mean CDW also decreased, from 99.8 ± 69.5 to 75.0 ± 55.1 mg/dL/kg over the 2 months. There were no significant changes in sCR, BUN, UA, and FBS. Mean TC increased from 187.5 ± 51.4 to 194.3 ± 43.4 mg/dL, and mean HDL-C changed from 53.7 ± 12.0 to 56.1 ± 11 mg/dL. There were no episodes of rejection or infection.

Conclusions

We conclude that switching from Prograf to Graceptor is safe and has the advantage of improving adherence. It could also have a beneficial effect in controlling glycemic levels and the adverse effects of tacrolimus. In many cases (25%-30%), the minimum concentration of tacrolimus decreased after changing tablets. With Graceptor, the ratio of area under trough level to area under the curve (AUC) is low compared with Prograf, resulting in low C_min values of 1-2 ng/mL, and the AUC for Graceptor is very similar to that for Prograf.     

Early post‐transplant conversion from tacrolimus to belatacept for prolonged delayed graft function improves renal function in kidney transplant recipients

Prolonged delayed graft function (DGF) in kidney transplant recipients imparts a risk of poor allograft function; tacrolimus may be detrimental in this setting. We conducted a retrospective single center analysis of the first 20 patients converted to belatacept for prolonged DGF as part of a clinical protocol as a novel treatment strategy to treat prolonged DGF. Prior to conversion, patients underwent an allograft biopsy to rule out rejection and confirm tubular injury. The primary outcome was the estimated glomerular filtration rate (eGFR) at 12 months post‐transplant; secondary outcome was the change in eGFR 30 days post‐belatacept conversion. At 1 year post‐transplant, the mean eGFR was 54.2 (SD 19.2) mL/min/1.73 m². The mean eGFR on the day of belatacept conversion was 16 (SD 12.7) mL/min/1.73 m² and rose to 43.1 (SD 15.8) mL/min/1.73 m² 30 days post‐conversion (P<.0001). The acute rejection rate was 20% with 100% patient survival at 12 months post‐transplant. There was one graft loss in the setting of an invasive Aspergillus infection that resulted in withdrawal of immunosuppression and transplant nephrectomy. Belatacept conversion for prolonged DGF is a novel treatment strategy that resulted in an improvement in eGFR. Additional follow‐up is warranted to confirm the long‐term benefits of this strategy.