Bariatric Surgery Is Associated With Decreased Calcineurin Inhibitor Time in Therapeutic Range After Heart Transplantation.

Bariatric surgery (BSg) is an effective treatment for morbid obesity, but little is known about the outcomes of BSg patients who undergo orthotopic heart transplantation (OHT). The aim of this study was to determine if BSg alters calcineurin inhibitor (CNI) level variability after OHT. Data were collected from 58 consecutive patients who underwent OHT at a single center from 1/2018 to 4/2019: 4 with BSg prior to OHT (BSg + OHT) and 54 without prior BSg (OHT). CNI level, cardiac biopsy, and left ventricular ejection fraction (LVEF) data were collected during the first 6 months post-OHT. Comparisons were made for 3 measures of CNI variability: coefficient of variation, time in therapeutic range (TTR), and TTR by the Rosendaal method. A Pearson's correlation coefficient was calculated to assess the relationship between CNI TTR, episodes of rejection, and LVEF. The results show TTR was lower in BSg + OHT compared to OHT (12.5% vs 31.3%, P < .05). For the entire cohort, greater TTR correlated with fewer episodes of rejection (r = 0.31, P < .05). In conclusion, these findings suggest BSg + OHT patients may warrant closer monitoring of CNI levels post-OHT. Furthermore, episodes of rejection and LVEF were similar for BSg + OHT patients, indicating that BSg should not be a contraindication to transplant.

Calcineurin inhibitor-associated new-onset diabetes mellitus in chronic kidney disease treatment: a 4-year single-center cross-sectional study in China.

PURPOSE: To identify the risk factors of calcineurin inhibitor (CNI)-associated new-onset diabetes mellitus (NODM) in chronic kidney disease (CKD) treatment. METHODS: We retrospectively screened patients treated with CNIs in our hospital from January 2015 to December 2018. The inclusion criteria were as follows: a clear diagnosis of CKD and patients receiving CNI treatment. We compared patients with and without CNI-associated NODM. RESULTS: Ninety-eight of the 336 assessed patients met the inclusion criteria, 15 (15.3% [15/98]) of whom developed CNI-associated NODM. Multiple logistic regression analysis revealed that baseline glycosylated hemoglobin (OR=4.141; 1.024-16.743; p=0.046) and CNI trough concentration (1 year) (OR=1.028; 1.009-1.047, p=0.004) were independent risk factors for NODM. In contrast, glucocorticoid type (prednisone) (OR=0.075; 0.011-0.526, p=0.009) was identified as an independent protective factor for NODM. Using a receiver operating characteristic curve, a cutoff cyclosporin A trough concentration of 102.1 ng/mL was identified as a predictive factor of NODM. Univariate logistic regression showed that the incidence of diabetes was significantly higher in patients with baseline glycosylated hemoglobin in non-diabetic range but higher than 5.65% (10.2% vs. 29.2%, p=0.038). One NODM patient (6.7% [1/15]) recovered at 12.7 months after the onset of diabetes mellitus. CONCLUSIONS: We recommend that more attention be paid to patients with baseline glycosylated hemoglobin in non-diabetic range but higher than 5.65% during CKD treatment with CNIs. High trough concentrations of cyclosporin A, particularly those >102.1 ng/mL, contribute to NODM. CNI-associated NODM may be reversible in the treatment of CKD.

Optimal blood levels of (extended-release) tacrolimus in living donor kidney transplantation to prevent de novo donor-specific antibody production: A retrospective cohort study.

Chronic antibody-mediated rejection, caused by de novo donor-specific antibody (dnDSA) production, results in poor graft survival. To prevent dnDSA production, optimal blood levels of immunosuppressive drugs in living donor kidney transplant recipients were determined. A total of 772 recipients underwent living donor kidney transplantation between January 2008 and December 2017. Graft survival and risk factors for dnDSA production were investigated in 647 recipients. Optimal blood levels of tacrolimus (TAC) and extended-release TAC (TACER) were measured in recipients receiving steroids and mycophenolate mofetil, combined with TAC (n = 53) or TACER (n = 135). Receiver operating characteristic (ROC) curve analysis and comparisons between dnDSA-negative and dnDSA-positive recipients were carried out. The Kaplan-Meier method revealed significantly poor graft survival in dnDSA-positive recipients (P < 0.001). Cox regression models indicated calcineurin inhibitor withdrawal as a significant risk for dnDSA production (P < 0.001; hazard ratio 6.637; 95% confidence interval 2.667-6.517). Average trough levels of TAC and TACER in dnDSA-negative recipients were significantly higher than those in dnDSA-positive recipients (4.88 vs 3.69 ng TAC/ml, P = 0.023, and 4.60 vs 3.85 ng TACER/ml, P = 0.001). ROC curve analysis indicated 4.325 and 3.990 ng/ml as the best trough levels under TAC- and TACER-based regimens, respectively, to prevent dnDSA production (areas under the curve: 0.788 and 0.813, respectively). Maintenance of the trough levels of TAC > 4.325 ng/ml and TACER > 3.990 ng/ml may prevent dnDSA production.

Pharmacokinetics and Biodistribution of Tacrolimus after Topical Administration: Implications for Vascularized Composite Allotransplantation.

AIM: The high doses of oral tacrolimus (TAC) (1,2) necessary to prevent acute rejection (AR) after vascularized composite allotransplantation (VCA) are associated with systemic adverse effects. The skin is the most antigenic tissue in VCA and the primary target of AR. However, the short-term use of topical TAC (Protopic®), as an off-label adjunct to oral TAC, to treat AR episodes pro re nata (PRN), has yielded inconsistent results. There is lack of data on the pharmacokinetics and tissue distribution of topical TAC in VCA, that hampers our understanding of the reasons for unreliable efficacy. Toward this goal, we evaluated the ability of topical TAC to achieve high local tissue concentrations at the site of application with low systemic concentrations. MATERIALS AND METHODS: We assessed the pharmacokinetics and tissue distribution of topical TAC (Protopic®, 0.03%) after single or repeated topical application in comparison to those after systemic delivery in rats. Animals received a single topical application of TAC ointment (Group 1) or an intravenous (IV) injection of TAC (Group 2) at a dose of 0.5 mg/kg. In another experiment, animals received daily topical application of TAC ointment (Group 3), or daily intraperitoneal (IP) injection of TAC (Group 4) at a dose of 0.5 mg/kg for 7 days. TAC concentrations in blood and tissues were analyzed by Liquid Chromatography-Mass Spectrometry (LC/MS-MS). RESULTS: Following single topical administration, TAC was absorbed slowly with a Tmax of 4 h and an absolute bioavailability of 11%. The concentrations of TAC in skin and muscle were several folds higher than whole blood concentrations. Systemic levels remained subtherapeutic (< 3 ng/ml) with repeated once daily applications. CONCLUSION: Topical application of TAC ointment (Protopic®, 0.03%) at a dose of 0.5 mg/kg/day provided high concentrations in the local tissues with low systemic exposure. Repeated topical administration of TAC is well tolerated with no local or systemic adverse effects. This study confirms the feasibility of topical application of TAC for site specific graft immunosuppression and enables future applications in VCA.

Tacrolimus Intrapatient Variability, Time in Therapeutic Range, and Risk of De Novo Donor-Specific Antibodies.

BACKGROUND: Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself. METHODS: We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non-dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years. RESULTS: Patients with CV >44.2% and TTR <40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P < 0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with patients with CV >44.2% and TTR ≥40% (high intrapatient variability and optimal TTR), while the latter patients had similar risk to patients with CV <44.2% (lower intrapatient variability). CONCLUSIONS: These data suggest that previously reported immunologic risk associated with high TAC intrapatient variability is due to time outside of therapeutic range rather than variability in and of itself when evaluating absolute non-dose-corrected TAC levels irrespective of reason or indication.

Posttransplant Calcineurin Inhibitors Levels and Intrapatient Variability Are Not Associated With Long-term Outcomes Following Liver Transplantation.

BACKGROUND: There is an interest in understanding the association between early calcineurin inhibitors exposure post-liver transplantation (LT) and long-term outcomes. We aimed to analyze this association exploring median calcineurin inhibitor levels and intrapatient variability (IPV) in a multicenter, retrospective cohort. METHODS: Tacrolimus (Tac) and Cyclosporine (CsA) levels obtained during the first 15 days post-LT were collected. High immunosuppression (IS) was considered as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration higher than 10, 250, or 1200 ng/mL, respectively, or a peak of Tac >20 ng/mL. Optimal IS was defined as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration levels between 7 and 10, 150 and 250, or 800 and 1200 ng/mL. Low IS was defined as below the thresholds of optimal IS. IPV was estimated during the first 15 days post-LT. RESULTS: The study included 432 patients with a median follow-up of 8.65 years. IS regimen was based on either Tac or CsA in 243 (56.3%) and 189 (43.8%), respectively. There were no differences in terms of graft loss among low versus optimal and high IS groups (P = 0.812 and P = 0.451) nor in high versus low IPV (P = 0.835). Only viral hepatitis and arterial hypertension were independently associated with higher graft loss (hazard ratio = 1.729, P = 0.029 and hazard ratio = 1.570, P = 0.021). CONCLUSIONS: In contrast to what has previously been reported, no association was found between very early postoperative over IS or high IPV and long-term outcome measures following LT. Strategies aimed at reducing these long-term events should likely focus on other factors or on a different IS time window.

Clinical Pharmacokinetics and Impact of Hematocrit on Monitoring and Dosing of Tacrolimus Early After Heart and Lung Transplantation.

The calcineurin inhibitor tacrolimus is an effective immunosuppressant and is extensively used in solid organ transplantation. In the first week after heart and lung transplantation, tacrolimus dosing is difficult due to considerable physiological changes because of clinical instability, and toxicity often occurs, even when tacrolimus concentrations are within the therapeutic range. The physiological and pharmacokinetic changes are outlined. Excessive variability in bioavailability may lead to higher interoccasion (dose-to-dose) variability than interindividual variability of pharmacokinetic parameters. Intravenous tacrolimus dosing may circumvent this high variability in bioavailability. Moreover, the interpretation of whole-blood concentrations is discussed. The unbound concentration is related to hematocrit, and changes in hematocrit may increase toxicity, even within the therapeutic range of whole-blood concentrations. Therefore, in clinically unstable patients with varying hematocrit, aiming at the lower therapeutic level is recommended and tacrolimus personalized dosing based on hematocrit-corrected whole-blood concentrations may be used to control the unbound tacrolimus plasma concentrations and subsequently reduce toxicity.

Assessment of rejection risk following subtherapeutic calcineurin inhibitor levels after pediatric heart transplantation.

CNIs are the mainstay of immunosuppressive therapy after pediatric HTx. While regular laboratory surveillance is performed to ensure blood levels are within targeted range, the risk of acute rejection associated with subtherapeutic CNI levels has never been quantified. This is a retrospective single-center review of 8413 CNI trough levels in 138 pediatric HTx recipients who survived >1 year after HTx. Subtherapeutic CNI levels were defined as <50% of the lower limit of target range. The risk of acute, late (>12 months post-transplant) rejection following recipients' subtherapeutic CNI levels was assessed using time-varying multivariable Cox proportional hazards analysis. We found that 79 of 138 recipients (57%) had at least one subtherapeutic CNI level on routine surveillance laboratories during a mean follow-up of 5.5 ± 3.6 years. Following an episode of subtherapeutic levels, 17 recipients (22%) had biopsy-proven rejection within the next 3 months; the majority (9/17) within the first 2 weeks. After presenting with subtherapeutic CNI levels, recipients incurred a 6.1 times increased risk of acute rejection in the following 3 months (HR = 6.11 [2.41, 15.51], P = <.001). Age at HTx, HLA sensitization, or positive crossmatch were not associated with acute late rejection, but rejection in the first post-transplant year was (HR 2.61 [1.27, 5.35], P = .009). Thus, maintaining therapeutic CNI levels is the most important factor in preventing acute rejection in recipients who are >12 months after pediatric HTx. Recipients who present with subtherapeutic CNI levels on surveillance monitoring are 6.1 times more likely to develop rejection in the following 3 months.

Effect of CYP3A5 and ABCB1 Gene Polymorphisms on Tacrolimus Blood Concentration in Renal Transplant Recipients.

BACKGROUND: Tacrolimus (Tac) is a calcineurin inhibitor (CNI). Its therapeutic range is narrow and pharmacokinetic properties vary among patients. CYP3A5 and MDR1 single-nucleotide polymorphisms (SNPs) are the most effective polymorphisms that play an significant role in the pharmacokinetics of Tac. METHODS: We investigated the influence of CYP3A5 (A6986G) and MDR1 (C3435T) gene polymorphisms on Tac trough concentration (C0), dose requirements (mg/kg), and dose-adjusted concentrations (ng/mL per mg/kg/d). CYP3A5 [*1/*1 (expresser), *1/*3 (expresser); *3/*3 (non-expresser)] and MDR1 (CC, CT, TT) gene polymorphisms were determined by allele-specific polymerase chain reaction in 67 adult Turkish renal transplant patients. The Tac dose (mg/kg/d) and C0 of each patient was acquired from the patient's file and dose-adjusted concentrations (ng/mL per mg/kg/d) were calculated at the 1st, 3rd, 6th, and 12th months after transplantation. The correlated serum hematocrit, platelet, urea, creatinine, and albumin were also determined. RESULTS: The CYP3A5*1/*3 and CYP3A5*3/*3 allelic frequencies were 5.97% and 94.03%, respectively. There were no patients with the CYP3A5*1/*1 genotype. Tac dose was significantly lower in *3/*3 genotype than in *1/*1 genotype (3rd and 6th months: p ≤ 0.001; 12th month: p ≤ 0.05). Dose-adjusted Tac concentration was statistically higher in the *3/*3 genotype than in *1/*1 genotype at the 3rd and 6th months (p ≤ 0.05). The allelic frequencies of MDR1 CC, CT, and TT were 26.87%, 49.25%, and 23.88%, respectively. No statistically significant differences were detected between MDR1 genotypes and in all analyzed laboratory parameters. CONCLUSIONS: CYP3A5 but not MDR1 genetic polymorphisms affected the Tac pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods can be used for selecting the initial dose to individualize immunosuppressive therapy.

Correlation between gene polymorphism and blood concentration of calcineurin inhibitors in renal transplant recipients: An overview of systematic reviews.

BACKGROUND: To provide an overview of systematic reviews and meta-analyses (SRs/MAs) of the correlation between genetic polymorphisms and blood concentrations of calcineurin inhibitors (CNIs) in recipients of renal transplant. METHODS: Databases including Medline, EMBase, The Cochrane Library (Issue 7, 2016), the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, the China Science and Technology Journal Database, and the Wan Fang Database were searched for SRs/MAs of the correlation between genetic polymorphisms and blood concentrations of CNIs in renal transplant recipients from inception to July 2016. Two reviewers independently screened the literatures and extracted data, then the AMSTAR measurement tool was used to assess the methodological quality of SRs/Mas included in the overview. RESULTS: Fourteen SRs/MAs met the inclusion criteria. The most commonly reported genotype was CYP3A53/3, which was strongly associated with cyclosporine A (CsA) and tacrolimus (FK506). MDR1 C3435T CC was also associated with CNI use, especially with CsA therapy. Other less commonly reported genotypes such as CYP3A41B, MDR1 C1236T CC, and MDR1 G2677T/A GG also affected the blood concentrations of CNIs. CONCLUSIONS: Our overview showed that polymorphisms influence the blood concentrations of CNIs, which suggests the necessity to monitor these concentrations in patients with genotypes that affect dose-adjusted trough concentrations (C0/D) or dose-adjusted peak concentrations (C2/D) to regulate the dosage for individual administration. Because of the limited number of included studies, these findings should be verified in more high-quality studies.

Immunosuppressive Drug Levels in Liver Transplant Recipients: Impact in Decision Making.

To prevent rejection, liver transplant providers largely base their management decisions on their clinical impression and pharmacokinetics. Clinical impression relies on assessing graft function, liver enzymes, and biopsy. High immunosuppressive drug levels, although minimizing rejection, are related to significant side effects such as nephrotoxicity and metabolic syndrome, contributing to long-term morbidity and mortality. Similarly, levels that are lower than necessary can decrease the rate of side effects with a potential toll on rejection and graft survival. Herein, the authors present an update on immunosuppressive drug level monitoring and manipulation strategies according to different scenarios and time from transplant. They also provide a brief overview of next level immunosuppression monitoring strategies that aim to properly balance rejection rates with drug side effect profiles.

Measurement of calcineurin activity in peripheral blood mononuclear cells by ultra-high performance liquid chromatography-tandem mass spectrometry. Renal transplant recipients application (pharmacodynamic monitoring).

BACKGROUND: Therapeutic drug monitoring of calcineurin inhibitor, tacrolimus (TAC), is routinely used in post-transplantation. Currently, measurement of calcineurin activity has been proposed as a promising clinical tool to evaluate efficacy and to optimize drug dosing. The main aim of our study was to develop a method to measure phosphatase calcineurin activity (CNA) in peripheral blood mononuclear cells (PBMCs) by ultra-high performance liquid chromatography-tandem mass spectrometry and to validate it following FDA and EMA guidelines. METHODS: This methodology is based on monitoring the Ca2+-dependent dephosphorylation of a phosphopeptide substrate. CNA was evaluated in 5 healthy volunteers and in 5 renal transplant patients receiving twice-daily formulation of TAC before drug intake. Moreover, we studied pharmacodynamic effect of TAC and blood concentrations of TAC in different drug dose intervals (0, 1, 3, 6 and 12 h). RESULTS: Our results showed linearity in the range 0.04-2.00 µM with a lower limit of quantification of 0.04 µM. Coefficients of variation and absolute relative biases were <4.3% and 10.3%, respectively. The mean recovery for peptide was 91.6 ±â€¯4.0%. Matrix effect study displayed ion suppression, and no carry-over and interferences were observed. There were no differences in CNA between healthy and TAC-treated patients. Furthermore, CNA showed maximum inhibition at 1 h after drug intake when TAC reached the highest blood concentration. CONCLUSIONS: This method improves the extraction phase of PBMCs and achieves faster determination compared to other techniques, bringing us closer to be applied in daily laboratory practice.

Effectiveness and safety of sofosbuvir-based therapy against chronic hepatitis C infection after successful kidney transplantation.

BACKGROUND: Direct-acting antivirals (DAAs), including sofosbuvir (SOF), are recommended for treatment of chronic hepatitis C virus (HCV) infection. However, few studies have investigated the effectiveness and safety of new DAAs in kidney transplant recipients (KTRs). OBJECTIVES: To assess the effectiveness and safety of SOF-based therapy in stable KTRs. PATIENTS AND METHODS: Forty KTRs were treated with SOF-based regimens. Rapid, end-therapeutic, and sustained virologic responses were assessed, as was liver stiffness by elastometry. Safety was monitored by measuring the estimated glomerular filtration rate (eGFR), blood hemoglobin (Hb) concentration, proteinuria, and blood trough levels of calcineurin inhibitors (CNIs). Other side effects were also recorded. RESULTS: The effectiveness of DAAs was 100% at all time points. The therapy did not significantly influence eGFR or proteinuria, but significantly decreased mean blood Hb levels (13.5 ± 2.0 vs 11.6 ± 1.9, respectively, P < 0.001), which required a dose reduction or cessation of ribavirin (RBV) in 50% of patients. A profound, significant decrease in initial CNI concentrations was also observed during treatment in the majority of patients within the first month of therapy. CONCLUSIONS: In this cohort of KTRs, the new SOF-based therapies were characterized by 100% effectiveness and good safety profiles. However, in patients co-treated with RBV, close blood Hb monitoring and early RBV dose reduction are necessary. In the majority of KTRs, antiviral therapy leads to a substantial and early decrease in CNIs levels, thus frequent measurement of CNI levels is necessary during SOF-based therapy.

Variability of the Mammalian Target of Rapamycin Inhibitors Is Correlated With Long-Term Renal Graft Survival.

BACKGROUND: Many studies demonstrate the relationship between the high intrapatient variability of calcineurin inhibitor (CNI) levels and poor long-term renal graft outcome. Our objective is to analyze the intrapatient variability observed in the mammalian target of rapamycin inhibitors (mTOR-i) blood levels, to compare the variability of sirolimus (SRL) with that of everolimus (EVL) in kidney transplant patients converted to an mTOR-i, and to analyze whether the coefficient of variation (CV) was correlated with long-term graft survival. METHODS: We analyzed 279 adult renal transplant patients converted to an mTOR-i. CV was calculated using at least 3 blood trough levels between 3 and 18 months postconversion. RESULTS: The mean and median CV of the entire group was 25.54% and 23.7%, respectively. SRL and EVL mean CV was 23.8% and 27.1% (P = .03), respectively. The group of patients into the last tertile with CV> 28.52% presented a lower death-censored graft survival (75.26% vs. 93.01%, P < .0001) with a mean follow-up of 66.5 months. CONCLUSION: The CV of mTOR-i is correlated with long-term renal graft survival, so it should be considered a prognostic factor. SRL has a lower CV than EVL in renal transplant patients converted to mTOR-i in the stable posttransplant phase.

Cyclosporine A trough concentrations are associated with acute GvHD after non-myeloablative allogeneic hematopoietic cell transplantation.

Low plasma CsA concentrations (<300-350 ng/mL) early following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of developing acute graft-versus-host disease (aGvHD). Nevertheless, the current optimal target trough concentration for CsA following HSCT is considered to be 200-400 ng/mL. Here, we performed a retrospective analysis of a homogeneous group of 129 patients who received HSCT after non-myeloablative conditioning, and we analyzed the impact of CsA trough concentration measured during the first four weeks (CsA W1-4) on the incidence aGvHD, relapse-free survival (RFS), non-relapse mortality (NRM), overall survival (OS), and toxicity. The 180-day incidence of grade II-IV aGvHD was 25% (32/129 patients). In multivariate analysis the incidence of grade II-IV aGvHD was significantly lower among patients with a CsA W1-4 concentration ≥350 ng/mL compared to patients with a concentration <350 ng/mL (18% versus 38%, respectively; P = 0.007), with a hazard ration (HR) of 0.38 (95% CI: 0.19-0.77). In contrast, we found no correlation between CsA trough concentration and RFS, NRM, or OS. Moreover, we found an increased incidence of hypomagnesemia at higher CsA concentrations, but no difference in the incidence of acute renal toxicity, hepatic toxicity, or electrolyte imbalance. Interestingly, 30% of patients experienced hyponatremia with no apparent cause other than the use of CsA, with urinalysis suggesting SIADH as the underlying cause. Our findings suggest that a CsA trough concentration of 350-500 ng/mL might be more appropriate in the first month following non-myeloablative HSCT.

Change in Mycophenolate and Tacrolimus Exposure by Transplant Vintage and Race.

OBJECTIVES: Although both tacrolimus and mycophenolate have improved outcomes after kidney transplant, studies regarding effects of exposure on outcomes, specifically related to racial disparities, are sparse. MATERIALS AND METHODS: In this 8-year longitudinal cohort study of adult kidney transplant recipients, mycophenolate and tacrolimus levels were compared across transplant vintage stratified by non-African Americans versus African Americans. Data were analyzed with standard univariate tests and multivariable regression models. RESULTS: Our study included 1217 patients (transplanted from 2005-2013) who had tacrolimus and myco-phenolate exposure data, with follow-up through 2015 (53.7% were African Americans). Mean mycophenolate dose was 1672 ± 463 mg/day during the first 3 years posttransplant. Although transplant vintage did not appreciably impact mycophenolate dosing in non-African Americans (0.7 mg/day/y; P = .903), doses significantly decreased in African Americans across transplant vintage (-20.5 mg/day/y; P < .001). Rate of mycophenolate being held or discontinued based on transplant vintage significantly increased in African Americans but did not change in non-African Americans. At the beginning of the study, mean tacrolimus levels were lower in African Americans; however, levels then slightly decreased in non-African Americans (-0.03 ng/mL/y; P = .279) and slightly increased in African Americans (+0.03 ng/mL/y; P = .247), with similar levels by 2013. Higher tacrolimus levels were protective against rejection in African Americans only but were protective against death-censored graft loss in both race/ethnicity groups. Mycophenolate dosing had no appreciable impact on outcomes in African Americans, but higher mycophenolate dosing was a significant risk factor for death-censored graft loss in non-African Americans. CONCLUSIONS: Tacrolimus and mycophenolate exposure levels have significantly changed over time and differed by race/ethnicity. In non-African Americans, those transplanted more recently tended to have lower tacrolimus but similar mycophenolate exposure. Although mycophenolate exposure in African Americans has recently decreased, tacrolimus has increased. Differences in outcomes likely reflect improved understanding of immunosuppressant tolerability by recipient race/ethnicity.

Comparative analysis for optimizing the modified release tacrolimus (Advagraf) after kidney transplantation: A prospective randomized trial.

Immunosuppression management in clinical transplantation aims to balance delivery of efficacy against adverse reactions using therapeutic drug monitoring. Adherence to posttransplant immunosuppressive medications and minimizing variability in drug exposure are important considerations in preventing rejection and maximizing overall transplant outcomes. The availability of once-daily tacrolimus may add a potential benefit by simplifying immunosuppressive regimens, though improving compliance among transplant recipients. The aim of our study is to investigate the safety and efficacy of the once-daily formulation of tacrolimus (Advagraf) against the usually used twice daily tablets (Prograf). A prospective randomized trial 1:2 was designed for 99 consecutive live-related renal transplant recipients who received their grafts at a single center (study group, Advagraf, 33 recipients and control group, Prograf, 66 recipients). The demographic data were homogeneous among both groups regarding donors and patients' characteristics. Posttransplant hypertension, infection, malignancy, and diabetes mellitus were comparable among both groups. Renal function and rejection episodes showed no statistical significance among recipients of both groups. Despite slight higher Advagraf unit doses, there was no statistical difference regarding the tacrolimus trough levels, between the two groups. Our singlecenter experience revealed that the availability of once-daily tacrolimus formulation could give potential benefit of improved medication compliance and better allograft outcomes by decreasing pill burden and thereby simplifying dosing schedule, Advagraf was non-inferior to twice-daily tacrolimus regarding safety and efficacy. Although being nonsignificant, a trend for better kidney function was noted in this short-term study in the Advagraf group, so long-term follow-up is needed to verify this.

Lower tacrolimus trough levels in the late period after living donor liver transplantation contribute to improvements in long-term clinical outcomes.

BACKGROUND: Previous studies have emphasized the need to reduce tacrolimus (TAC) trough levels in the early post-liver transplantation (LT) period. However, whether late-period TAC trough levels influence the long-term outcomes of liver recipients is not clear. METHODS: We enrolled 155 adult liver recipients survived more than 3 years after living donor liver transplantation because of non-malignant liver diseases. The maintenance immunosuppressive regimens were TAC monotherapy and combined therapy with mycophenolate mofetil. Patients were divided into three groups according to their late-period TAC trough levels: < 3 ng/mL group, 3-5 ng/mL group, and  >5 ng/mL group. The complications and adverse effects of TAC were analyzed. RESULTS: Each group showed similar rejection, graft loss and mortality. Patients achieved the < 5 ng/mL state in less than 4 years had fewer new-onset diabetes, hyperlipidemia, de novo malignancies, and hepatitis B virus recurrence; the complications of renal dysfunction and hypertension rates were the same among these 3 groups. CONCLUSIONS: Collectively, our findings indicated that lower TAC trough levels in the late period of liver transplantation are safe, improve the long-term outcomes.

Prediction of Tacrolimus Exposure by CYP3A5 Genotype and Exposure of Co-Administered Everolimus in Japanese Renal Transplant Recipients.

While tacrolimus and everolimus have common metabolic pathways through CYP3A4/5, tacrolimus is metabolized solely by CYP3A4 in recipients with the CYP3A5*3/*3. The purpose of this study was to evaluate how the area under the blood concentration-time curves (AUC) of tacrolimus could be predicted based on CYP3A5 genotype and the AUC of everolimus in renal transplant patients taking both drugs. The dose-adjusted AUC (AUC/D) of tacrolimus and everolimus were calculated at one month and one year after transplantation. Significant correlations between the AUC/D of tacrolimus and everolimus were found for patients with the CYP3A5*1 allele or CYP3A5*3/*3 at both one month and one year. At both stages, the determination coefficients were higher and the slopes of regression equations were larger for patients with CYP3A5*3/*3 compared to the CYP3A5*1 allele. A good correlation between single doses of tacrolimus and everolimus was found for CYP3A5*3/*3 patients at 1 year after transplantation (r = 0.794, p < 0.001). The variability of the AUC0-24/D of tacrolimus for each CYP3A5 genotype could be predicted based on the AUC0-12/D of everolimus. Clinicians may be able to comprehensively carry out the dose adjustments of tacrolimus and everolimus based on relationship with AUCs of both drugs in each CYP3A5 genotype.