Prolonged-release Formulation Of Tacrolimus Research Articles

A single‐center, open‐label, randomized cross‐over study to evaluate the pharmacokinetics and bioavailability of once‐daily prolonged‐release formulations of tacrolimus in de novo liver transplant recipients

BackgroundThe narrow therapeutic window of tacrolimus (Tac) requires intense drug monitoring to achieve adequate efficacy while minimizing dose‐related toxicities. Once‐daily formulations of Tac (LCP‐Tac and PR‐Tac) have been recently designed for higher bioavailability and a more consistent exposure over time, as opposed to the twice‐daily, administered immediate‐release formulation of Tac (IR‐Tac).MethodsThis single‐center, open‐label, randomized cross‐over pharmacokinetic (PK) study compares extended‐release LCP‐Tac with the prolonged‐release formulation of tacrolimus (PR‐Tac) in adult de novo liver transplant recipients. Eligible patients were screened and randomized 1:1 to the two treatment arms up to 30 days after liver transplantation. Patients were administered either LCP‐Tac or PR‐Tac for 14 days followed by another 14‐day time interval of the other once‐daily Tac medication. A 24hr‐PK profile was obtained at the end of each time interval.ResultsNine patients (45%) completed the study resulting in a total of 18 Tac PK profiles. Overall, the profile of the mean concentrations indicated a flattened kinetic of LCP‐Tac compared to PR‐Tac, especially in the first 3 h after drug intake. The average cumulative dose per day to achieve equivalent trough levels was approximately 25% lower for LCP‐Tac (8.7 mg) than for PR‐Tac (11.7 mg). LCP‐Tac resulted in a longer tmax and fewer peak‐to‐trough fluctuations compared to PR‐Tac.ConclusionDespite methodological weaknesses that limit the conclusions, we have found a more consistent drug exposure for LCP‐Tac in de novo LT recipients. LCP‐Tac demonstrated a greater bioavailability compared to PR‐Tac.

Differential Effect of a Continental Breakfast on Tacrolimus Formulations With Different Release Characteristics.

Food reduces tacrolimus bioavailability after immediate-release tacrolimus (IR-Tac) and after a new prolonged-release tacrolimus formulation (PR-Tac), when using a high-fat breakfast, but the effects of a continental breakfast on PR-Tac are unknown. In an open-label, 4-phase, randomized, 2-sequence, crossover pharmacokinetic trial, 36 healthy volunteers (18 females) received single 5-mg tacrolimus doses as PR-Tac and as IR-Tac fasted or with a standardized continental breakfast. Tacrolimus pharmacokinetics were analyzed using noncompartmental methods and mixed-model analysis of variance. The continental breakfast significantly decreased average tacrolimus exposure (area under the plasma concentration-time curve) with both preparations (IR-Tac, 67%; 90% confidence interval [CI], 59%-75%; P < .01; and PR-Tac, 79%; 90%CI, 70%-89%; P < .01) with a nonsignificant difference between both preparations (P = .10). The maximum concentration (Cmax ) and the time to maximum concentration (tmax ) were significantly affected only after IR-Tac (Cmax IR-Tac, 39%; 90%CI, 34%-45%; P < .01; and PR-Tac, 87%; 90%CI, 76%-101%; P = .11; tmax IR-Tac, 212%, 90%CI, 179%-252%; P < .01; and PR-Tac, 101%; 90%CI, 86%-120%; P = .89), which was significantly different between both preparations (P < .01). Considering switching from IR-Tac to PR-Tac, predicted dose requirements differed according to the timing of drug intake in relation to food. In conclusion, a continental breakfast decreased average tacrolimus exposure of both preparations to a similar extent. Cmax and tmax were affected only after IR-Tac. The effect of a standardized continental breakfast on PR-Tac was considerably smaller than previously reported effects of a high-fat breakfast on PR-Tac.

Conversion From Twice-Daily to Once-Daily Tacrolimus in Stable Kidney Graft Recipients.

Immunosuppression has a pivotal role in kidney transplantation. The new prolonged-release formulation of tacrolimus was developed to provide a more convenient once-daily dosing to improve patient adherence. We selected 60 stable kidney transplant recipients who underwent tacrolimus conversion in our unit. Conversion was made on a 1 mg:1 mg basis in 66.7% of patients (n= 40) and on a 1 mg:1.1 mg basis in the remaining 33.3% (n= 20). Clinical and analytical data at conversion and postconversion was analyzed retrospectively to evaluate the efficacy and safety of conversion from tacrolimus twice-daily to once-daily formulation. A significant reduction in tacrolimus blood levels requiring an increase in tacrolimus daily dose was observed postconversion. Postconversion tacrolimus blood level reduction >25% was significantly higher in the conversion group 1 mg:1 mg basis (P=.004). In patients converted 1 mg:1 mg, female sex and higher tacrolimus level at conversion were significant risk factors for a reduction >25% in tacrolimus blood levels after conversion. No significant change was detected between mean glomerular filtration rate at conversion (57 mL/min) and at 3, 6, and 9 months postconversion. Once-daily tacrolimus at similar doses to the twice-daily formulation is an efficient and safe treatment option. Conversion made on 1 mg:1.1 mg basis seems advantageous at least in some patients.

Factorial Analysis on Individual Variability of Tacrolimus Extended- Release Formulation Pharmacokinetics in the Early Period after Renal Transplantation-Factors for AUTL/AUC Decrease

Background: We have often observed that the blood trough concentration (Ct) of the once-daily, prolonged-release formulation of tacrolimus (Graceptor®; GRC) becomes unstable, and it is difficult to adjust it in the early period after transplantation. Consequently, we compared the relationships between pharmacokinetic parameters and influencing factors in a group of GRC-treated patients compared with those in a group of Prograf® (PRG)-treated patients. Methods: The study included 8 patients who were newly treated with GRC and 44 patients who were newly treated with PRG. We performed 24-hour therapeutic drug monitoring to compare the relationships between pharmacokinetic parameters, including the area under the curve (AUC), the ratio of the area under the trough level (AUTL)/AUC to indicate the relationships among AUCs, peak concentration (Cp), and Ct. The Cp/Ct values, and dose/body weight (UC/ [D/BW]) values reflected bioavailability and the influencing factors; number of days after transplantation and Dose/BW in the GRC-treated and PRG-treated patients. Results: The Cp/Ct values were higher and the AUTL/AUC and AUC corrected by dose/body weight (AUC/[D/BW]) values were lower with a low number of days after transplantation (particularly within 20 days) and a large dose than a high number of days after transplantation and a small dose in the GRC-treated patients. No such associations were observed in the PRG-treated patients. Conclusion: Care is required when using GRC as there is a tendency for Cp to increase owing to rapid absorption within 20 days after transplantation. Blood levels may be unstable and side effects may be more prevalent in some patients. Moreover, the utilization rate is low and the dose is high in such patients; therefore, unstable gastrointestinal function caused by a variety of factors may play a role in the early period after transplantation.

Tacrolimus prolonged release (Envarsus®): a review of its use in kidney and liver transplant recipients.

Tacrolimus prolonged release (Envarsus®; henceforth referred to as tacrolimus PR) is a new, once-daily, prolonged-release tacrolimus formulation, utilizing a drug delivery technology designed to enhance the bioavailability of drugs with low water solubility by creating a solid solution of the drug. This article reviews the pharmacological properties of tacrolimus PR and its clinical efficacy and tolerability in adult kidney and liver transplant recipients. In phase III trials, tacrolimus PR was noninferior to tacrolimus immediate release (IR; twice daily) in both de novo and stable, previously treated kidney transplant recipients, and had a similar tolerability profile. Preliminary efficacy data from phase II trials in de novo and stable, previously treated liver transplant recipients imply that tacrolimus PR is effective in these patient groups; however, more data would be of interest. Pharmacokinetic analyses demonstrated that tacrolimus PR is associated with a higher bioavailability, reduced peak-trough concentration fluctuation ratio, lower mean values for percentage degree of fluctuation and percentage degree of swing, and a longer time to maximum concentration than tacrolimus IR. Tacrolimus PR is a promising addition to the treatment options available for kidney and liver transplant recipients.

Comparison of Once-Daily and Twice-Daily Low-Dose Tacrolimus in Living Related Kidney Transplantation -Prospective Trial of Once-Daily vs. Twice-Daily Tac -3 Years Second Report.

Background; A prolonged-release formulation of Tacrolimus (Tac-QD) has been developed to allow once-daily dosing with a similar safety and efficacy profile to that of twice-daily tacrolimus (Tac-BD). Previously, we reported a comparison of the safety and pharmacokinetics between Tac-QD and BD in the early phase after kidney transplantation. In this study, we report longer-term results in the same recipient population 3 years after the aforementioned prospective study. Materials and methods; Between November 2009 and January 2011, 130 consecutive adult patients were randomized to receive either low-dose Tac-QD or Tac-BD. The transplant operation was cancelled due to other reasons after enrollment in this study in 9 cases. During the 3- to 5-years' observation period, the treatment was switched from Tac-BD to Tac-QD in 5 cases, and from Tac-QD to Tac-BD in 2 cases. The drug itself was switched from tacrolimus to cyclosporine in 2 cases. One patient died and 5 cases lost their grafts. In the remaining 106 cases included as the subjects of this study, we examined the patient and graft survival rates, the incidence rates of graft rejection, the serum tacrolimus trough level, and the total oral dose of tacrolimus. Results; The patient survival rates are 100% and 98% in the QD and BD groups. The graft survival rate is 98% in both groups. The current tacrolimus dose is 2.9±1.7 mg/day in the QD group and 2.4±1.2 mg/day in the BD group (P=0.32). The mean tacrolimus trough level is 5.1±0.9 ng/ml in the QD group and 5.0±1.1 ng/ml in the BD group (P=0.81). There is no statistically significant difference in the graft function between the QD and BD groups (serum creatinine level; 1.2±0.4 mg/dl in the QD group vs. 1.1±0.2 mg/dl in the BD group; P=0.55). The incidence rate of acute/chronic T cell-mediated rejection until 3 years after Tx was 10% (2/19) in the QD group and 12 % (3/25) in the BD group (P=0.95). The incidence rate of acute/chronic antibody-mediated rejection until 3 years after Tx was 5% (1/19) in the QD group and 8% (2/25) in the BD group (P=0.87). There has been no significant difference in the graft rejection rate, CNI toxicity, incidence of BK nephropathy and recurrence of IgA nephropathy between the two groups. Conclusion; The clinical efficacy and safety profile of Tac-QD and Tac-BD are almost the same, even 3 to 5 years after kidney transplantation.

A UK analysis of the cost of switching renal transplant patients from an immediate-release to a prolonged-release formulation of tacrolimus based on differences in trough concentration variability

Background and aims:Randomized controlled trials have shown that a once-daily prolonged-release (PR) tacrolimus formulation (PR tacrolimus; Advagraf), is non-inferior to a twice-daily immediate-release (IR) tacrolimus formulation (IR tacrolimus; Prograf) in terms of biopsy-proven acute rejection, graft failure and mortality in renal transplant recipients. However, relative to IR tacrolimus, PR tacrolimus exhibits reduced tacrolimus trough concentration variability, which has been associated with reduced graft failure. Based on these data, the present study evaluated the cost of switching UK renal transplant patients from IR tacrolimus to PR tacrolimus.Methods:UK-specific data on acute rejection, graft failure, and mortality were used to construct a budget impact model to assess the costs of switching from IR tacrolimus to PR tacrolimus on a 1:1 mg:mg basis. The model assumed that 3.1% of patients on PR tacrolimus had high tacrolimus trough concentration variability compared with 17.4% on IR tacrolimus, based on a study comparing PR tacrolimus and IR tacrolimus pharmacokinetics. A relative graft failure risk of 2.38 was applied to high variability patients based on data from a tacrolimus variability study in which 10/148 patients with low variability experienced graft failure, compared with 24/149 in the high variability group. Cost data were taken from the British National Formulary and 2012–2013 NHS tariff information.Results:The mean per-patient cost (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was GBP 26,941 (standard deviation [SD] = GBP 2765) with PR tacrolimus vs GBP 30,356 (SD = GBP 3085) for IR tacrolimus over a 5-year period, corresponding to a saving of GBP 3415 (SD = GBP 516) per patient or GBP 341,500 in a hypothetical 100-patient transplant center. Cost savings were driven primarily by lower dialysis costs resulting from the lower proportion of PR tacrolimus patients with high tacrolimus trough concentration variability (leading to lower graft failure risk).Limitations:The main limitation of the study was the use of heterogeneous data sources to capture the effect of within-patient variability on graft failure. The most important difference between the studies was the definition of the threshold between low and high within-patient variability. This was explored in sensitivity analyses in which the inter-arm difference in the inter-arm proportions of patients with high and low variability was abolished.Conclusions:Converting UK renal transplant recipients from IR tacrolimus to PR tacrolimus was associated with lower pharmacy and dialysis costs.

OSAKA Trial

BackgroundThe once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes.MethodsThis open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy-confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m2. The prespecified noninferiority margin was 12.5%.ResultsThe per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan–Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, −1.6%; 95% confidence interval [CI], −12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, −3.5%; 95% CI, −13.6% to 6.6%) or Arm 4 (difference, −7.1%; 95% CI, −16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m2) was the main determinant of composite-endpoint efficacy failure across all arms.ConclusionsIn patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD.

Comparison of Pharmacokinetics and Pathology for Low-Dose Tacrolimus Once-Daily and Twice-Daily in Living Kidney Transplantation

A prolonged-release formulation of tacrolimus (Tacrolimus QD) was developed to allow once-daily dosing and to have similar safety and efficacy profiles to twice-daily tacrolimus (Tacrolimus BID). This study compared the pharmacokinetics (PK) and renal pathology by protocol biopsy in de novo living kidney transplant recipients treated with either low-dose Tacrolimus QD or Tacrolimus BID. Between November 2009 and January 2011, 102 consecutive adult patients were randomized to receive either low-dose Tacrolimus QD or Tacrolimus BID. All patients underwent PK study and protocol biopsy on postoperative day 14. Additional protocol biopsies were performed between 6 and 12 months after renal transplantation. During the 1-year follow up, the incidence of biopsy-proven acute rejection and toxic tubulopathy was low and similar in both groups. Twenty-four hours area under the curve (AUC0-24) was not different in both groups (285 ± 78.7 and 281 ± 62.4 ng hr/mL in Tacrolimus QD and Tacrolimus BID, respectively). C0 was well correlated with AUC0-24 in both groups and AUC0-24 between 260 and 280 in the Tacrolimus QD group was achieved by 6 to 8 ng/mL of C0. Acute nephrotoxicity was less than 10% in both groups without any clinical manifestation. Clinical efficacy, safety, and PK profile of Tacrolimus QD is same as those of Tacrolimus BID.

Once Daily Prolonged-Release Tacrolimus in de Novo Renal Transplantation: A Single-Center Experience

Background: A prolonged release formulation of tacrolimus may prove to be especially beneficial for transplant recipients in regard to compliance. The aim of this study was to show the results obtained in our center, analyzing the safety, efficacy, blood trough levels, and drug doses. Methods: We retrospectively reviewed data from 22 recipients of renal transplantation which were performed between February 2009 and November 2011. All recipients received initial immunosuppression with once daily tacrolimus assossiated with mycophenolic acid, steroids, and basiliximab. Efficacy and safety variables were collected as the incidence of acute rejection episodes, patient and graft survivals, kidney function as well as incidences of diabetes mellitus. Moreover, we collected result of therapeutic drug monitoring (TDM) of tacrolimus in de novo kidney transplants. Results: Patient and graft survivals were 100%, and the mean serum creatinine level was 1.49 ± 0.77 mg/dL. The incidence of biopsy proven acute rejection episodes was 18.2% (n = 4). Although the rate of diabetes mellitus de novo was 23.8% (n = 5), all recipients lead to improve with no medication. Although we experienced a case of nephrotoxicity causing acute renal failure in early post renal transplantation period, renal function improved by modifying dose of tacrolims. One recipient developed polyoma virus nephropathy. There was a strong correlation between AUC0-24 and Cmin. Conclusion: Once daily prolonged-release tacrolimus have advantage to improve adherence. The good results for patient and graft survival with few side effects make it a useful drug for de novo kidney transplantation

No change in insulin sensitivity in renal transplant recipients converted from standard to once-daily prolonged release tacrolimus

New-onset diabetes after transplantation may be associated with the use of tacrolimus (Tac) causing impaired insulin release or reduced insulin sensitivity. Such effects have not been studied in renal transplant recipients receiving traditional twice-daily tacrolimus (TacBID) and then compared to the new once-daily prolonged release formulation of tacrolimus (TacOD). We performed a prospective crossover study of 20 stable non-diabetic renal transplant recipients. All patients underwent one hyperglycaemic clamp on TacBID (3.8 ± 2.2 mg/day) and a new clamp 4-6 weeks after a 1:1 mg/day switch to TacOD (4.0 ± 2.8 mg/day). Tac trough concentrations decreased from 6.6 ± 2.9 to 5.4 ± 1.4 μg/mL (P = 0.037) and Tac max from 21.3 ± 8.4 to 15.2 ± 3.5 μg/L (P = 0.001). Tac AUC(0-24) was reduced from 265 ± 112 to 218 ± 47 μg × h/L (P = 0.12). The hyperglycaemic clamp did not detect any change in insulin sensitivity index after conversion [0.26 ± 0.21 versus 0.26 ± 0.25 μmol/min/kg/(pmol/L insulin), P = 0.99] nor any change in first (334 ± 274 versus 353 ± 248 μIU × min/mL, P = 0.41) or second phase insulin secretion (224 ± 155 versus 263 ± 210 μIU × min/mL/mmol glucose, P = 0.60) on TacBID versus TacOD. Conversion from standard TacBID to TacOD on a 1:1 mg basis is safe. In spite of a reduced Tac exposure, there was no change in insulin release or sensitivity in renal transplant recipients.

Advagraf De Novo in Liver Transplantation: A Single-Center Experience

Advagraf, a prolonged release formulation of tacrolimus, is administered once daily in the morning. The aim of this study was to show the results obtained in our center, analyzing the safety, efficacy, blood trough levels, and drug doses. Methods We analyzed 50 consecutive recipients of a first liver transplantation with 6 months follow-up. Efficacy and safety variables were collected as the incidence of acute rejection episodes, patient and graft survivals, kidney function as well as incidences of diabetes mellitus and arterial hypertension de novo. Results The incidence of biopsy proven acute rejection episodes was 10% ( n = 5), none 7 of which were steroid resistant and all resolved favorably. The rate of diabetes mellitus de novo was 22% ( n = 11), 7 of whom required insulin. Hypertension developed in 9 patients (18%), all of whom were treated with a single drug. The mean serum creatinine level was 1.08 ± 0.25 mg/dL, with 3 patients (6%) displaying a value ≥ 1.5 mg/dL. Patient and graft survivals were 100%. Conclusion Advagraf is an effective immunosuppressant in liver transplantation with a low incidence of biopsy-confirmed acute rejection episodes. The good results for patient and graft survival with few side effects make it a useful drug for de novo liver transplantation.

Pharmacokinetics of Once- Versus Twice-Daily Tacrolimus Formulations in Kidney Transplant Patients Receiving Expanded Criteria Deceased Donor Organs: A Single-Center, Randomized Study

Background Noncompliance to immunosuppressive treatment is 1 of the risk factors for kidney graft loss. The once-daily, prolonged-release tacrolimus formulation may improve treatment adherence. We sought to compare the pharmacokinetics of both tacrolimus formulations in older de novo recipients of a cadaveric renal transplant from an expanded-criteria donor. Patients and Methods This randomized study included 27 patients (14 on once daily prolonged-release formulation [QD] and 13, on the twice-daily formulation [BID]), who were treated with 0.1 mg/kg per day of tacrolimus (target blood level, 5–8 ng/mL) mycophenolate mofetil prednisone and basiliximab induction. Results At 24 hours, incombination with the blood levels were 4.70 ± 2.50 versus 4.70 ± 3.04 ng/mL ( P = NS). There were no significant differences in the AUC 0–24 of tacrolimus (QD/BID) at 3 days (300.8 ± 60.15 vs 287.7 ± 125.78 ng.h/mL) or 21 days (303.05 ± 99.79 vs 275.26 ± 75.37 ng.h/mL), nor in blood levels (ng/mL) at 1 month (8.76 ± 2.46 vs 8.8 ± 1.89), 3 months (7.30 ± 1.72 vs 8.80 ± 1.89) and 6 months (7.19 ± 1.89 vs 6.60 ± 1.71). At 3 days, there was a strong correlation between AUC 0–24 and C min both for tacrolimus QD ( r = .872) and BID ( r = 1.0). The incidences of acute rejection episodes were: 0% versus 16.6%; graft survivals, 100% versus 92.3% ( P = NS); and patient survivals, both 100%. Conclusion For older de novo recipients of kidneys from expanded criteria donors tacrolimus QD is comparable to the same dose in the BID formulation with similar at least short-term transplant outcomes.

Reduced C0 Concentrations and Increased Dose Requirements in Renal Allograft Recipients Converted to the Novel Once-Daily Tacrolimus Formulation

Recently, a once-daily prolonged release formulation of tacrolimus (TacOD) has been approved for the prevention of renal allograft rejection. Studies reported equivalent area under the concentration-time curve0-24 and predose trough (C0) concentrations when compared with the standard twice-daily tacrolimus (Tac) formulation. Hence, the package insert advices a 1:1 mg conversion. Here, we report our independent experience with conversion to TacOD according to the manufacturer's instructions. Retrospective single-center study evaluating the evolution of C0 concentrations and dose requirements after conversion to TacOD in 284 renal allograft recipients. Potential clinical, biochemical, and genetic determinants of changes in C0 concentrations and dose requirements after conversion were explored in univariate and multivariate analyses. After conversion, C0 concentrations decreased significantly (-1.36+/-2.51 microg/L or -12.66%+/-24.36%, P<0.0001). In 38.3% of patients, this decrease exceeded 20%. TacOD dose was increased in 52.5% of patients. Average dose requirements increased to 0.71+/-1.78 mg/day or 14.68%+/-28.87% (P<0.0001). In 28.0% of patients, dose requirements increased more than 20%. Dose changes were more profound in patients converted within 1 year after transplantation, and in this subgroup (n=78), higher creatinine and lower hemoglobin levels were associated with a larger increase in dose requirements in multivariate analysis (r=0.35, P<0.0001). Despite dose adjustments, average C0 concentrations remained 9.09%+/-28.85% lower after conversion (P<0.0001). Conversion from standard twice-daily tacrolimus formulation to TacOD on a 1:1 mg basis results in reduced Tac C0 concentrations and increased dose requirements. Thus, conversion is not as straightforward as suggested by the manufacturer, and converted patients should be monitored strictly until stable C0 concentrations are achieved.