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The use of tacrolimus (Tac) may be involved in the development of new-onset diabetes after transplantation (NODAT) in a dose-related manner. This study aimed to evaluate the effects of a standard twice-daily formulation of Tac (TacBID) vs. the once-daily slow-release formulation (TacOD) on the basal insulin resistance indexes (Homa and McAuley), and related metabolic parameters, in a cohort of kidney transplant patients. We retrospectively evaluated 20 stable renal transplant recipients who were switched from TacBID to TacOD. Blood levels of Tac were analyzed at one-month intervals from 6 months before to 8 months after conversion. Moreover, Homa and McAuley indexes, C-peptide, insulin, HbA1c, uric acid, triglycerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol serum levels and their associations with Tac levels were evaluated. We observed a significant decrease in Tac exposure (8.5 ± 2 ng/mL, CV 0.23 vs. 6.1 ± 1.9 ng/mL, CV 0.31, TacBID vs. TacOD periods, p < 0.001) and no significant changes in Homa (1.42 ± 0.4 vs. 1.8 ± 0.7, p > 0.05) and McAuley indexes (7.12 ± 1 vs. 7.58 ± 1.4, p > 0.05). Similarly, blood levels of glucose, insulin, HbA1c, lipids, and uric acid were unchanged between the two periods, while C-peptide resulted significantly lower after conversion to TacOD. These data suggest that in kidney transplant recipients, reduced Tac exposure has no significant effects on basal insulin sensitivity indexes and metabolic parameters.

A once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed in response to the problem of nonadherence. However, there have been no data available about the efficacy of Tac QD conversion from intravenous Tac (Tac i.v.) in allogeneic hematopoietic stem cell transplantation (allo-SCT). We analyzed the pharmacokinetics (PK) of Tac QD in allo-SCT recipients. A total of 10 patients with hematological malignancies who received allo-SCT from unrelated donors were enrolled. Patients received Tac i.v. at 0.03 mg/kg a day before transplantation. Administration of Tac i.v. was converted to Tac QD at a 1:4 ratio when the patients had recovered from regimen-related gastrointestinal toxicity and could tolerate oral medication. After conversion, six out of 10 patients (60 %) showed a sustained decrease in Tac exposure and required dose adjustment. The conversion from Tac i.v. to Tac QD should be performed under close medical supervision. Area under the curve (AUC) and the trough of Tac QD showed a correlation, and the trough should be maintained above 7.5 ng/ml to provide an adequate AUC. Although four patients received bone marrow from an HLA DRB1 1 antigen-mismatched unrelated donor, no patients developed grade III-IV acute graft-versus-host disease (GVHD). The modification of Tac QD to maintain a whole-blood trough concentration above 7.5 ng/ml may be as effective as Tac BID. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine the prevalence of nonadherence in a cohort of renal transplant recipients (RTRs) and to evaluate prospectively whether more intense clinical surveillance and reduced pill number enhanced adherence. Patients and methods: The study was carried out in 310 stable RTRs in whom adherence, life satisfaction, and transplant care were evaluated by specific questionnaires (time 0). The patients under tacrolimus (TAC; bis in die [BID]) were then shifted to once-daily TAC (D-TAC) to reduce their pill burden (Shift group) and were followed up for 6 months to reevaluate the same parameters. Patients on cyclosporin or still on BID-TAC constituted a time-control group. Results: The prevalence of nonadherence was 23.5% and was associated with previous rejection episodes (P<0.002), and was inversely related to Life Satisfaction Index, anxiety, and low glomerular filtration rate (minimum P<0.03). Nonadherent patients were significantly less satisfied with their medical care and their relationships with the medical staff. A shift from BID-TAC to D-TAC was performed in 121 patients, and the questionnaires were repeated after 3 and 6 months. In the Shift group, a reduction in pill number was observed (P<0.01), associated with improved adherence after 3 and 6 months (+36%, P,0.05 versus basal), with no change in controls. Decreased TAC trough levels after 3 and 6 months (-9%), despite a slight increase in drug dosage (+6.5%), were observed in the Shift group, with no clinical side effects. Conclusion: The reduced pill burden improves patients' compliance to calcineurin-inhibitors, but major efforts in preventing nonadherence are needed. [ABSTRACT FROM AUTHOR]

Background. 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).Methods. 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).Results. 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 AUC0–24 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.Conclusions. 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. [ABSTRACT FROM AUTHOR]

Background: A prolonged-release formulation of tacrolimus for once-daily administration (tacrolimus QD) has been developed. This phase II, open-label, multicenter, prospective single-arm study compared the pharmacokinetics (PK) of tacrolimus in stable heart transplant patients before and after conversion from twice-daily tacrolimus (tacrolimus BID) to tacrolimus QD. Methods: Heart transplant recipients (≥6 months after transplant), previously maintained on tacrolimus BID–based therapy, received tacrolimus BID from Days 1 to 7 and were converted on a 1:1 (mg/mg) basis to tacrolimus QD. Five 24-hour PK profiles were collected (Days 1, 7, 8, 14, 21). Safety parameters were also evaluated. Results: Of 85 patients, 45 (50.6%) completed all 5 evaluable PK profiles. Steady-state tacrolimus area under the curve, 0 to 24 hours (AUC0–24) and minimum concentration (Cmin) were comparable for both formulations, with treatment ratio means of 90.5% (90% confidence intervals [CI], 86.4%–94.6%) and 87.4% (95% CI, 82.9%–92.0%), respectively (acceptance interval, 80%–125%). There was good correlation between AUC0–24 and Cmin for tacrolimus QD (r = 0.94) and BID (r = 0.91). The relationship between these 2 parameters was also similar. Conclusions: This study provides evidence for successful conversion from tacrolimus BID to QD on a 1:1 (mg/mg) total daily dose basis. Approximately one-third of patients may require dose adjustments. Both formulations were well tolerated, with stable renal function during the study. Adverse events were reported by approximately one-tenth of patients receiving tacrolimus BID and a quarter of those who received QD. [ABSTRACT FROM AUTHOR]

Background: Tacrolimus trough levels (TTL) during the first weeks after liver transplantation (LT) have been related with long-term renal function and hepatocellular carcinoma recurrence. Nevertheless, the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate., Aim: To evaluate the effect of TTL during the first month on the long-term outcomes after LT., Methods: One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied. Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy. Patients were classified into 2 groups according to their mean TTL within the first month after transplantation: ≤ 10 ( n = 98) and > 10 ng/mL ( n = 57). Multivariate analyses were performed to assess risk factors for patient mortality., Results: Mean levels within the first month post-transplant were 7.4 ± 1.7 and 12.6 ± 2.2 ng/mL in the ≤ 10 and > 10 groups, respectively. Donor age was higher in the high TTL group 62.9 ± 16.8 years vs 45.7 ± 17.5 years ( P = 0.002) whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7% vs 15.8% ( P = 0.02). Recipient features were generally similar across groups. After a median follow-up of 52.8 mo (range 2.8-81.1), no significant differences were observed in: Mean estimated glomerular filtration rate ( P = 0.69), hepatocellular carcinoma recurrence ( P = 0.44), de novo tumors ( P = 0.77), new-onset diabetes ( P = 0.13), or biopsy-proven acute rejection rate (12.2% and 8.8%, respectively; P = 0.50). Eighteen patients died during the follow-up and were evenly distributed across groups ( P = 0.83). Five-year patient survival was 90.5% and 84.9%, respectively ( P = 0.44), while 5-year graft survival was 88.2% and 80.8%, respectively ( P = 0.42). Early TTL was not an independent factor for patient mortality in multivariate analyses., Conclusion: Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients., Competing Interests: Conflict-of-interest statement: MG is a member of advisory boards and has received honoraria from Astellas, Novartis and Chiesi. JB has received honoraria from Astellas and Novartis. AV has received honoraria from Astellas and Novartis. All other authors have no conflicts to declare., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Despite the therapeutic equivalence between twice-daily and once-daily tacrolimus, patient safety after conversion is still a concern. We reviewed 218 liver transplantation (LT) patients who converted twice-daily to once-daily tacrolimus between May 2011 and January 2014. Thirty (13.8%) patients had adverse events after conversion, with a liver function test (LFT) abnormality being the most common adverse event (n = 17). Despite the decrease in serum tacrolimus of > 30% after conversion, none of the patients who were converted to a dosage ratio (once-daily tacrolimus dosage: twice-daily tacrolimus dosage) > 1 had an LFT abnormality. Most patients with an LFT abnormality improved after increasing the once-daily tacrolimus dosage (n = 2), returned to a previous medication, and/or added another immunosuppressant (n = 15). One patient had acute cellular rejection, which improved after steroid pulse treatment, and another patient had graft failure. In patients with a dosage ratio ≤ 1, the conversion time within 5 years after LT was the only significant risk factor for an LFT abnormality after conversion (odds ratio: 11.850, 95% confidence interval: 1.321-106.325, P = 0.027). In conclusion, the dosage ratio and time after LT should be carefully considered during conversion from twice-daily to once-daily tacrolimus., Competing Interests: The authors have no potential conflicts of interest to disclose.

Introduction: We assessed our clinical experience with de novo kidney transplant recipients from living donors who received once-daily tacrolimus (OD TAC). In addition, we investigated tacrolimus pharmacokinetics and compared the dose of tacrolimus in de novo kidney transplant patients treated with OD TAC or twice-daily tacrolimus (BD TAC)., Material and Methods: Ten patients (3 ABO incompatible, 2 preemptive), who had received a living donor kidney transplant at our hospital since February, 2009, received OD TAC with mycophenolate mofetil, methylprednisolone, and basiliximab. OD TAC doses were adjusted to maintain tacrolimus trough levels in the range of 9-12 ng/mL. We assessed clinical and pharmacokinetic profiles. We compared average total daily dose of tacrolimus between the OD TAC and BD TAC groups., Results: Patient survival and graft survival rates were 100% at 15.7 months. Acute rejection was not found clinically. The protocol biopsies (week 3 and month 3) did not reveal biopsy-proven acute rejection, either. No calcineurin inhibitor toxicity occurred. Doses in the OD TAC and BD TAC groups at week 3 posttransplant were 0.308 mg/kg/day and 0.149 mg/kg/day, respectively., Conclusions: OD TAC appears to have efficacy and safety equivalent to that of BD TAC. However, a larger dose of OD TAC compared to that of BD TAC may be required during the early period after kidney transplantation.