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.     

Long-term interleukin-2 assessment after conversion from a twice-daily to once-daily tacrolimus regimen in stable kidney recipients

Conversion to tacrolimus (Tac) to once daily (Tac-O) formulation is commonly followed by a 20% reduction in Tac trough levels in the first month. It is not associated with modifications of renal function but there is the issue of its effects on inflammatory cytokines and on subclinical rejection. The aim of our study was to evaluate long-term interleukins (IL)-2 profiles in stable renal transplant patients after Tac-O conversion. We enrolled 10 stable kidney transplant patients converted to Tac-O. Tac trough levels, serum creatinine concentrations, glomerular filtration rate using the Modification of Diet in Renal Disease formula, C-reactive protein, IL-2 levels, and clinical assessments were performed monthly for 6 months before and 12 months after conversion. Despite the significant reduction in Tac trough levels, we did not observe alterations suggestive of clinical or subclinical acute rejection.     

Conversion of stable kidney transplant recipients from a twice-daily prograf to a once-daily tacrolimus formulation: a short-term study on its effects on glucose metabolism

Background

The adverse effects of tacrolimus are known to play major roles in posttransplantation diabetes mellitus (PTDM). In the present study, we investigated the effects of conversion from a twice-daily (Tac BID) to a once-daily prolonged release of tacrolimus formulation (Tac OD) on glucose metabolism in stable kidney transplant recipients.

Patients and Methods

In this prospective study, 26 patients converted from Tac BID to the same milligram-milligram daily dose of Tac OD were examined for the effects on renal function, drug trough levels, and glucose metabolism over a 4-week period.

Results

Conversion from Tac BID to Tac OD on a 1:1 mg basis resulted in a significant decrease in tacrolimus trough levels, but no significant changes in renal function. At 4 weeks after conversion, a homeostasis model assessment of β-cell function, and hemoglobin A1c (HbA1c) decreased significantly.

Conclusions

This study demonstrated a significant reduction in tacrolimus trough levels after switching from Tac BID to Tac OD, which increased insulin secretion and decreased HbA1c, suggesting that it may decrease the frequency of PTDM among stable renal transplant recipients.     

Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481).     

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。     

Two years postconversion from a prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients

Tacrolimus extended-release (XL) is a once-daily formulation recently developed to reduce the frequency of dosing for patients currently using the twice-a-day formulation of tacrolimus (TAC). As reported previously, 67 kidney transplant recipients were safely converted (1:1 mg basis, total daily dose) from TAC twice-a-day to XL once-daily in the morning and were maintained on an am dosing regimen of XL using the same therapeutic monitoring and patient care techniques currently employed with TAC. The 2-year postconversion patient (100%) and graft (98.5%) survival, incidence of biopsy-confirmed acute rejection (6.0%), incidence of multiple rejections (1.5%), and safety profile (posttransplant diabetes, hyperlipidemia, hypertension, infections, renal dysfunction, hepatic dysfunction, and malignancies) were consistent with or more favorable than those previously reported for TAC twice-a-day.     

Interleukin-2 profiles shortly after tacrolimus conversion from a twice-daily to once-daily regimen

A number of studies have indicated that kidney recipients can be safely converted from the twice-daily formulation (Tac-T) to the same dose of a once-daily tacrolimus (TAC) regimen (Tac-O) based upon monitoring of renal function. Conversion from Tac-T to Tac-O is commonly followed by a reduction in Tac trough levels, estimated by some authors to be about 20%. These alterations seem to not be associated with a modification of graft function, but study of inflammatory cytokines would be useful. The aims of our study were to monitor Tac, C-reactive protein (CRP), and interleukin (IL)-2 levels as well as to evaluate renal function among stable renal transplant patients converted from a Tac-T to a Tac-O regimen. We enrolled 10 consecutive stable kidney transplanted patients. Tac trough levels, serum creatinine concentrations, glomerular filtration rates using the Modification of Diet in Renal Disease formula (MDRD), CRP, and clinical assessment were performed monthly for 6 months before and 3 months after the conversion. After conversion we observed a slight but not significant reduction in Tac trough level. Renal function evaluated by serum creatinine and MDRD as well as CRP were not significantly different after conversion. IL-2 levels remained stable after conversion. We identified a group of patients showing reduced Tac trough levels below the therapeutic range and a group with stable Tac levels. No significant differences were observed among the two groups before versus after the conversion. Our results did not show a modification of IL-2, CRP and renal function levels, at 3 months after conversion despite the lower Tac trough concentrations. The clinical meaning of Tac trough alterations is not clear. They might reflect inter- and intraindividual differences in the clearance of Tac as recently described. They did not seem to be associated with activation of an inflammatory pathway.     

Successful conversion from twice-daily to once-daily tacrolimus in liver transplantation: observational multicenter study

Dopazo C, Rodriguez R, Llado L, Calatayud D, Castells L, Ramos E, Molina V, García R, Fabregat J, Charco R. Successful conversion from twice‐daily to once‐daily tacrolimus in liver transplantation: observational multicenter study.
Clin Transplant 2012: 26: E32–E37.
© 2011 John Wiley & Sons A/S. Background: Compliance with immunosuppressive therapy in liver transplant patients is critical to prevent acute organ rejection and/or late graft loss. Strategies to simplify the therapeutic regimen may improve adherence. Aim: To evaluate the safety and efficacy of conversion from a twice‐daily to once‐daily tacrolimus formulation in adult liver transplant patients. Patients and methods: This prospective observational multicenter study included 187 liver transplant patients with at least 10 months post‐transplant follow‐up, no rejection episodes in the last three months, and creatinine levels <2 mg/dL. Conversion from a twice‐daily to a once‐daily formulation was based on a 1:1 proportion. Results: Median age was 61 yr (range: 28–80 yr); 64% were men and 36% women. The main indications for liver transplant were alcoholic cirrhosis in 30%. Median conversion time was 55 months (range: 10–215 months). Serum tacrolimus levels decreased at one month after conversion (pre‐conversion levels = 5.4 ± 3.0 ng/mL vs. post‐conversion levels = 4.4 ± 2.4 ng/mL, p = 0.013); however, these values normalized at six months post‐conversion with no changes in liver function and rejection episodes were observed only in two patients. Conclusion: Conversion from a twice‐daily to a once‐daily tacrolimus formulation is a safe, effective strategy in the management of stable liver transplant patients.     

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

INTRODUCTION: Modified release (MR) tacrolimus is an extended release formulation administered once daily. The purpose of this pharmacokinetic (PK) study was to evaluate tacrolimus exposure in stable liver transplant recipients converted from Prograf twice a day to MR tacrolimus once daily. METHODS: This was an open-label, multicenter study with a single sequence, four-period crossover design. Eligible patients were 18 to 65 years of age, >6 months posttransplant with stable renal and hepatic function and receiving stable doses of Prograf twice a day for >2 weeks prior to enrollment. Patients received Prograf twice a day on days 1 to 14 and 29 to 42. Patients were converted to the same milligram-for-milligram daily dose of MR once daily on days 15 to 28 and 43 to 56. Twenty-four-hour PK profiles were obtained on days 14, 28, 42, and 56. Laboratory and safety parameters were also evaluated. RESULTS: Of 70 patients, 62 completed all four PK profiles. The AUC0-24 of tacrolimus was comparable for Prograf twice a day (days 14 and 42) and MR tacrolimus once daily (days 28 and 56). The 90% confidence intervals for MR tacrolimus versus Prograf at steady state (days 28 and 56 vs days 14 and 42) was 0.85 to 0.92 for AUC0-24. MR tacrolimus was well tolerated with a safety profile comparable to that of Prograf. AUC0-24 was highly correlated to Cmin for Prograf (day 14, r = .93; Day 42, r = .89) and for MR tacrolimus (day 28, r = .93; day 56, r = .92). Renal and liver function remained stable. One patient experienced acute rejection. CONCLUSION: The steady-state tacrolimus exposure of MR tacrolimus once daily is equivalent to Prograf twice a day after a milligram-for-milligram conversion in stable liver transplant recipients.     

Switch from twice-daily tacrolimus (Prograf) to once-daily prolonged-release tacrolimus (Advagraf) in kidney transplantation

Advagraf is a new modified-release once-daily formulation of tacrolimus. The aim of this study was to define the efficacy and safety of switching from Prograf to Advagraf immunosuppression in kidney transplant recipients. The switched dose ratio of Prograf to Advagraf was 1:1. Forty-one patients (34 men and 7 women) were switched at 36.6 ± 16.1 months after kidney transplantation. All patients maintained stable renal function and the conversion. In 16 subjects it was possible to withdraw steroid administration after obtaining adequate Advagraf blood levels, among whom 14 remained steroid free. Adverse events, including dizziness and tinnitus, were reported in 1 patient, who was reverted to Prograf. One patient who was receiving triple therapy with low tacrolimus blood levels experienced are acute rejection episode. The switch to Advagraf was safe and efficacious in kidney transplant recipients with or without steroid administration. Moreover, interruption of steroid was possible and well tolerated after achieving adequate stable blood levels with Advagraf.     

Cardiovascular risk profile after conversion from cyclosporine A to tacrolimus in stable renal transplant recipients

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in renal recipients. In addition to steroids, cyclosporine A (CsA) has been implicated in contributing to increased cardiovascular risk. Conversion from CsA to tacrolimus (TAC) has been shown to improve hyperlipidemia and hypertension, but little is known about the differential effects of CsA versus TAC on other cardiovascular risk factors. We investigated overall cardiovascular risk profile after conversion from CsA to TAC. METHODS: This was an open-label, single-arm prospective study; 22 adult renal recipients who were receiving CsA-based immunosuppression with serum total cholesterol greater than 200 mg/dL more than 1 year after transplantation were enrolled. CsA was replaced by TAC. Blood pressure, fasting lipid profile, homocysteine, fibrinogen, C-reactive protein, hemoglobin A1c, and creatinine were measured at baseline and at 3 and 6 months after conversion. RESULTS: There was a significant improvement in fibrinogen (366 +/- 81 - 316 +/- 65 mg/dL, P <0.001), total cholesterol (250 +/- 50 - 207 +/- 29 mg/dL, P <0.001), and low-density lipoprotein cholesterol (155 +/- 43 - 121 +/- 24 mg/dL, P <0.001) after conversion. No new onset or worsening of diabetes mellitus was observed after conversion. There were no significant differences in HDL cholesterol, triglycerides, homocysteine, C-reactive protein, hemoglobin A1c levels, serum creatinine, mean blood pressure, and mean number of antihypertensive medications required before and after conversion. CONCLUSIONS: Our results indicate that conversion to low-dose TAC may be preferable over CsA for chronic maintenance immunosuppression because it improves the overall cardiovascular risk profile without any apparent adverse effects.     

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.     

Renal function and safety in stable kidney transplant recipients converted from immediate-release to prolonged-release tacrolimus

This multicenter, open, phase IIIb study assessed short-term efficacy, safety and dose adjustments in adult stable renal transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients receiving unchanged tacrolimus BID for ≥ 12 weeks were enrolled, and after 6-weeks, converted from tacrolimus BID to QD (morning dose) on a 1 : 1 (mg : mg) total daily dose basis, for a further 12 weeks. Primary endpoint: change in steady-state creatinine clearance between treatment phases. Secondary endpoints: biopsy-proven acute rejection (BPAR), patient and graft survival, safety. 128 patients enrolled (mean age 48.9 years; time post-transplant 48.9 months); 91 evaluated for the primary endpoint. Mean total daily dose was 0.06 mg/kg (BID) and 0.07 mg/kg (QD); 79.1% required one/no dose changes post-conversion to maintain recommended blood-trough levels; average dose increase was small (0.6-0.7 mg/day) with more dose increases in patients on the lowest tacrolimus BID doses. Renal function remained stable and non-inferiority of tacrolimus QD against tacrolimus BID was demonstrated. There were no BPAR episodes; patient and graft survival were 100%. Adverse events were few; none led to dose modifications/discontinuation. Tacrolimus BID to tacrolimus QD conversion is straightforward and does not compromise renal function in stable kidney transplant patients in the short term.     

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.     

Effects of switching from twice-daily to once-daily tacrolimus formulation on quality of life, anxiety, and transplant benefit perception after kidney transplantation

Objective

This study investigated whether switching from the twice-daily (Prograf; TAC) to the once-daily formulation of tacrolimus with extended release (Advagraf; XL) affected quality of life, anxiety, and transplant benefit perception after allogeneic kidney transplantation.

Methods

After local Institutional Review Board approval, 78 adult patients prescribed twice-daily tacrolimus for ≥1 year after kidney transplantation were asked to participate in this study. All patients were evaluated at T0 (before the switch), and the 49 who accepted the change were reassessed after 6 months (T1). The following tests were used: (State and Trait Anxiety Inventories Y1 and Y2, (Psychologic General Well-Being Index), and modified Transplant Effect Questionnaire for posttransplantation symptoms. Blood samples for laboratory profiles and determinations of drug concentrations were obtained throughout the study period.

Results

There were no significant differences between the psychologic variables at T0 among patients who switched from TAC to XL (n = 49) versus those who did not participate (n = 29). Eight of the 49 patients who accepted the drug conversion were reswitched to TAC because of adverse events. At T1, the remaining switched patients (n = 41) showed an increase in the disclosure of having undergone transplantation (P < .05) versus nonswitched patients; whereas reswitched patients (n = 8) showed less positivity and well-being (P < .05) compared with those who remained in the switched regimen.

Conclusion

The findings suggested increased disclosure of having undergone transplantation among patients who decided to switch from TAC to XL.