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Adequate tacrolimus blood exposure is crucial in the early post-renal transplant period and a gut epithelial barrier integrity may play a role. We prospectively investigated several markers of intestinal permeability in recent kidney transplant recipients (KTRs) treated with different tacrolimus extended-release formulations. Within each of the 49 KTR pairs that received grafts from the same donor, an early randomized conversion was performed from twice-daily (Prograf) to once-daily tacrolimus formulation: Advagraf or Envarsus. Plasma zonulin, calprotectin, circulating lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (FABP-2), and CD-14 levels were measured. There was no difference in the recipient age, dialysis vintage, BMI, and residual diuresis between Advagraf and Envarsus groups. FABP-2 and LPS levels were significantly associated with tacrolimus trough level, 3-h level, and area under the curve (AUC) in the Envarsus but not in the Advagraf group. AUC was independently increased by LPS and decreased by age, FABP-2 concentration, and the use of Envarsus formulation as compared with Advagraf. Functional changes of gastrointestinal tract in patients treated with Envarsus may influence intestinal tacrolimus absorption to a greater extent than in Advagraf-treated KTRs and may lead to inadequate variability of tacrolimus exposure early after kidney transplantation.

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The calcineurin inhibitor (CNI) Tacrolimus (Tac) is the most prescribed immunosuppressant drug after solid organ transplantation. After renal transplantation (RTx) approximately 95% of recipients are discharged with a Tac-based immunosuppressive regime. Despite the high immunosuppressive efficacy, its adverse effects, narrow therapeutic window and high intra- and interpatient variability (IPV) in pharmacokinetics require therapeutic drug monitoring (TDM), which makes treatment with Tac a major challenge for physicians. The C/D ratio (full blood trough level normalized by daily dose) is able to classify patients receiving Tac into two major metabolism groups, which were significantly associated with the clinical outcomes of patients after renal or liver transplantation. Therefore, the C/D ratio is a simple but effective tool to identify patients at risk of an unfavorable outcome. This review highlights the challenges of Tac-based immunosuppressive therapy faced by transplant physicians in their daily routine, the underlying causes and pharmacokinetics (including genetics, interactions, and differences between available Tac formulations), and the latest data on potential solutions to optimize treatment of high-risk patients.

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Background and Purpose: Several formulations of tacrolimus are available, but evidence of the benefit of changing to the most recent formulations is lacking. Tacrolimus intra-patient variability (tacrolimus IPV) is an emerging risk factor associated with poor graft outcomes after solid organ transplantations. Here, we examined the modifications of tacrolimus IPV after switching to a different formulation of tacrolimus. Experimental Approach: We identified 353 solid organ transplant recipients that were switched in our center from immediate-release (IR-tacrolimus) or prolonged-release tacrolimus (PR-tacrolimus) to extended-release, LCP-tacrolimus (LCP-tacrolimus). Among them, 54 patients underwent at least 3 available tacrolimus blood concentrations before and after the switch, allowing us to investigate tacrolimus IPV. Key Results: The switch was considered as a safe procedure since only four of the 353 patients presented a graft rejection after the switch, and no patient was hospitalized for tacrolimus overdose. The tacrolimus IPV estimated by the coefficient of variation (CV-IPV) was stable before and after the switch to LCP-tacrolimus (CV-IPV: 29.0% (IQR 25-75 (15.5; 38.5) before and 24.0% (15.8; 36.5) after the switch, p = 0.65). Conclusion and Implications: Switching from IR- or PR-tacrolimus to LCP-tacrolimus is a safe procedure. However, the CV-tacrolimus IPV was not impacted by the change of formulation.

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High intra-patient variability (IPV) of tacrolimus levels is associated with poor long-term outcome after transplantation. We aimed to evaluate whether the number of regularly prescribed medications is associated with the tacrolimus IPV. We have studied 152 kidney transplant recipients (KTRs) with mean post-transplant time of 6.0 ± 3.1 years. The coefficient of variation (CV) as a measure of IPV was calculated in each individual patient. Data concerning the type and number of currently prescribed medications were collected. The participants were divided into four groups, based on the number of regularly prescribed drugs (≤3, 4-6, 7-9, ≥10 drugs, respectively). There was an increasing trend for median CV, proportional to the increasing number of medications [group 1: 0.11 (interquartile range, 0.08-0.14), group 2: 0.14 (0.01-0.17), group 3: 0.17 (0.14-0.23), group 4: 0.17 (0.15-0.30); p value for trend = 0.001]. Stepwise backward multivariate regression analysis revealed that the number of medications [partial correlation coefficient (rpartial) = 0.503, p < 0.001] independently influenced the tacrolimus IPV. Concomitant steroid or diuretics use increased IPV only in Advagraf-treated KTRs, whereas proton-pump inhibitor or statin use increased IPV in the Prograf group but not in the Advagraf group. A large number of concomitant medications significantly increases the tacrolimus IPV in stable KTRs.

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Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.

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Tacrolimus (TAC) is available as a twice-daily capsule (TAC-BID), once-daily capsule (TAC-QD), and once-daily tablet. Recipients with ABO-incompatible/anti-human leukocyte antigen (HLA)-incompatible transplantation were excluded in previous trials and have thus not been evaluated. We conducted a 5-year trial to determine whether TAC-QD is noninferior to TAC-BID for transplant outcomes. Adults who underwent de novo living kidney transplantation were randomly assigned (62 TAC-QD; 63 TAC-BID). We did not exclude ABO-/HLA- incompatible transplantation. TAC was initiated 7 days preoperatively (0.10 mg/kg/d). Mycophenolate mofetil, methylprednisolone, and basiliximab were administered. The primary endpoint was graft failure (non-censored for death). We performed a noninferiority test. The noninferiority margin was 10% in risk difference. Five-year graft failure rates were 6.5% and 9.5% for TAC-QD and TAC-BID, respectively (noninferiority, P = 0.009). The estimated glomerular filtration rates were similar between the groups (noninferiority, P < 0.001). TAC-QD did not have point estimates of risk difference above the inferiority margin in any assessed endpoints. However, a tendency of interaction was observed between biopsy-proven acute rejection and the follow-up period. In a living kidney transplant population with 40% of patients with ABO/HLA incompatibility, the effect of TAC-QD was not appreciably worse on various clinical transplant outcomes than that of TAC-BID over 5 years.

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BACKGROUND: The calcineurin inhibitor tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, clinical management of Tac therapy can be challenging because of its narrow therapeutic window and because many factors interfere with its metabolism. Therefore, therapeutic drug monitoring is used to adjust the dosage. METHOD: Recently, we were able to classify patients receiving tacrolimus into two major metabolism groups by simple calculation of the C/D ratio (expressed as the blood concentration normalized by the dose). RESULTS: We showed that the C/D ratio is significantly associated with the (renal) outcome of recipients after kidney and liver transplantation. CONCLUSION: These findings are interesting and relevant to transplant physicians and physicians interested in immunosuppressive therapy. We therefore review current state of the art aspects of tacrolimus pharmacokinetics including genetics or different tacrolimus formulations (twice-daily immediate-release tacrolimus capsules, once-daily extended- release tacrolimus capsules; novel once-daily tacrolimus tablets) and their possible clinical impact including practical considerations for clinicians.

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OBJECTIVES: To clarify the incidence rate of post-transplant diabetes mellitus and associated risk factors in Japanese kidney transplant recipients, and to explore which treatment components are most effective in reducing post-transplant diabetes mellitus. METHODS: We analyzed 849 Japanese non-diabetic adult recipients who had undergone living kidney transplantation and had received tacrolimus-based immunosuppression from 1996 to 2013 with a median follow-up of 5 years. RESULTS: In all, 127 patients developed post-transplant diabetes mellitus during the follow-up period. The incidence rate of post-transplant diabetes mellitus was 15.1% (95% confidence interval 12.7-17.5) at 5 years. Recipient age (hazard ratio 1.05, 95% confidence interval 1.05-1.06, P < 0.001 for every 5-year increase), obesity (hazard ratio 1.70, 95% confidence interval 1.06-2.73, P = 0.028), tacrolimus trough level at 2 weeks post-transplantation (hazard ratio 1.06, 95% confidence interval 1.03-1.09, P < 0.001 for a 1-ng/mL increase) and mycophenolate mofetil use (hazard ratio 0.46, 95% confidence interval 0.28-0.77, P = 0.003) were significant predictors of post-transplant diabetes mellitus. Estimated 5-year predicted incidence rate after adjusting for age and obesity was 9.4% for recipients with a low tacrolimus trough level, and receiving mycophenolate mofetil and 38.4% for recipients with a high tacrolimus trough level and not receiving mycophenolate mofetil. CONCLUSIONS: Post-transplant diabetes mellitus is a common complication in Japan, similar to that in other Western countries. The present results show that an appropriate immunosuppressive regimen with a combination of tacrolimus and mycophenolate mofetil can reduce the likelihood of developing post-transplant diabetes mellitus. Clinical trials are required to confirm these findings.

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BACKGROUND: Tacrolimus is metabolized by cytochrome P450 (CYP) 3A4 and 3A5. We investigated the influence of CYP3A5 polymorphism and concurrent use of azole antifungal agents (AZ) on the pharmacokinetics of a once-daily modified-release tacrolimus formulation (Tac-QD) in patients after hematopoietic stem cell transplantation (HSCT). DESIGN AND METHODS: Twenty-four patients receiving allogeneic HSCT were enrolled. Genotyping for CYP3A5*3 was done by a PCR-restriction fragment length polymorphism method. Trough blood concentrations (C0) of tacrolimus were measured by chemiluminescence magnetic microparticle immunoassay. Continuous infusion of tacrolimus was administered from the day before transplantation and was switched to Tac-QD after adequate oral intake. RESULTS: Thirteen patients had a CYP3A5*3/*3 genotype, and 11 patients had a CYP3A5*1/*1 or *1/*3 genotype. No significant difference was observed in daily dosages and the C0 of tacrolimus between the two genotype groups without AZ. However, in patients who were co-administered AZ, the C0 values of tacrolimus were higher in patients with the CYP3A5*3/*3 allele than with the CYP3A5*1 allele (P = 0.034), although daily doses of Tac-QD in patients with CYP3A5*3/*3 were significantly lower than those with the CYP3A5*1 allele (P = 0.041). The cumulative incidence of acute kidney injury was higher in patients with the CYP3A5*3/*3 than with the CYP3A5*1 allele when AZ was co-administered. The decrement for daily dosage of Tac-QD was significantly greater in patients expressing the CYP3A5*3/*3 than the CYP3A5*1 allele. CONCLUSIONS: CYP3A5 genotyping may be useful for safe and effective immunosuppressive therapy with Tac-QD in HSCT patients in whom the use of AZ is anticipated.

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BACKGROUND: There is a growing concern about the therapeutic equivalence of the generic tacrolimus formulation (GEN Tacrolimus) to the reference tacrolimus (REF Tacrolimus) in solid organ transplantation. METHODS: A prospective, randomized study of 126 de novo renal transplant patients was conducted to compare the efficacy, safety and pharmacokinetic (PK) profiles between GEN tacrolimus (n = 63) and REF tacrolimus (n = 63). The PK of tacrolimus was evaluated on Day 10 and 6 months under steady-state condition. Crossover study was carried out in 66 patients at 6 months. RESULTS: On Day 10, 117 patients completed PK profiles (54 GEN tacrolimus and 63 REF tacrolimus) and GEN tacrolimus showed comparable C(0) (9.8 ± 2.5 versus 9.7 ± 3.0 ng/mL, P = 0.80) but significantly higher dose-normalized C(max) (309.1 ± 191.9 versus 192.5 ± 95.2 ng/mL/mg/kg, P < 0.001). The dose-normalized AUC(0-12) tended to be higher in the GEN tacrolimus than in the REF tacrolimus group (1513.4 ± 935.4 versus 1262.5 ± 593.5 ng.h/mL/mg/kg, P = 0.084). Because of this early and high C(max) with a rapid decline in GEN tacrolimus concentration, the trough concentration was maintained lower than that of REF tacrolimus. At 6 months, GEN tacrolimus showed equivalent dose-normalized AUC(0-12) (1882.2 ± 935.6 versus 1718.1 ± 946.3 ng.h/mL/mg/kg, P = 0.429) but still higher dose-normalized C(max) (346.3 ± 184.4 versus 273.2 ± 148.9 ng/mL/mg/kg, P = 0.056), despite a reduced trough concentration (5.7 ± 1.6 versus 6.9 ± 2.2 ng/mL, P = 0.004). PK profiles evaluated at 9 months showed that generic substitution also resulted in an 'early and high C(max)'. Efficacy and safety data were comparable over the 9-month study period. CONCLUSIONS: Therapeutic equivalence and the PK of GEN tacrolimus should be evaluated in patients undergoing de novo renal transplantation.

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