Daily Tacrolimus Research Articles

Relationship Between Change Rate of Tacrolimus Clearance During Continuous Intravenous Infusion and Recipient Recovery at an Early Stage After Living Donor Liver Transplantation.

Tacrolimus clearance (CL) is significantly altered according to recovery of liver function at an early stage after living donor liver transplantation (LDLT). In this study, we aimed to examine the impact of the change rate from postoperative day (POD) 1 in CL (ΔCL) of tacrolimus during continuous intravenous infusion (CIVI) on recipient recovery. A tacrolimus population pharmacokinetic model on POD1 after LDLT was developed using Phoenix NLME 1.3. The CLPOD1 was calculated using the final model. The CLPOD4-7 was calculated by dividing total daily tacrolimus dose by the area under the concentration-time curve from 0 to 24h. Data were obtained from 57 LDLT recipients, along with 540 points (177 points on POD1, 363 points on POD4-7) of tacrolimus whole blood concentrations at CIVI. The median tacrolimus CL decreased from POD1 to POD4 (from 2.73 to 1.40L/h) and was then stable until POD7. Stepwise Cox proportional hazards regression analyses showed that the graft volume (GV)/standard liver volume (SLV) ratio (GV/SLV) and the tacrolimus ΔCLPOD6 were independent factors predicting early discharge (within 64days median value) of recipients after LDLT [hazard ratio (HR) = 1.041, P = 0.001 and HR = 1.023, P = 0.004]. The tacrolimus ΔCL during CIVI immediately after LDLT in each recipient was a useful indicator for evaluation of recovery at an early stage after LDLT.

Expected and Observed Glomerular Filtration Rates in Kidney Transplant Patients Converted to Once Daily Tacrolimus: 10 Years of Follow-up

The decline of allograft kidney function in the long term remains a significant issue in renal transplantation, with drug nephrotoxicity and cardiovascular complications as important risk factors. Our study aimed to evaluate the estimated glomerular filtration rate (eGFR) trend and metabolic cardiovascular risk factors over 10 years in a cohort of kidney transplant (KT) recipients converted from twice-daily (TD) tacrolimus (Tac) to once-daily (OD)-Tac.We enrolled 55 consecutive KT recipients who had been at the outpatient clinic between 2009 and 2011. Thirty-seven reached the 10-year follow-up. We compared the observed eGFR with the expected eGFR trend described in KT-recipients and monitored blood pressure and metabolic cardiovascular risk factors.The observed eGFR remained stable throughout the complete follow-up (P = .188). The observed decline of eGFR was significantly lower compared with the expected decline for KT patients (P < .001). The blood pressure was maintained within target values. The monitoring of plasma glucose levels demonstrated the stability of median values (P = .686), as well as cholesterol level (P = .250), high-density lipoprotein (HDL) cholesterol (P = .294), and triglycerides (P = .592) throughout the follow-up. The monitoring of tacrolimus plasma level demonstrated that median trough levels remained constant (median values 4.4-5.5 ng/mL) throughout the entire follow-up period (P = .149). We suggest that the reasonable control of metabolic risk factors for cardiovascular disease over long-term follow-up may significantly contribute to the preservation of eGFR compared with the decline expected in KT recipients.

Correction to: Once-Daily versus Twice Daily Tacrolimus in Kidney Transplantation: A Systematic Review and Meta-analysis of Observational Studies.

The row for study Jelassi et al. (2011) [28], where the Observational Period for ER-Tac reads June 2007-March 2010a and for IR-Tac reads N/A.

Once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in liver transplantation

ObjectiveFor patients who have received a kidney transplant, studies have shown that once-daily prolonged-release tacrolimus (TAC) has similar efficacy and safety to standard twice-daily dosing. The purpose of this study was to perform a meta-analysis to compare the effectiveness and safety of daily TAC (TAC qd) versus standard twice-daily TAC (TAC bid) administration in liver transplantation (LT). DesignMeta-analysis. Setting and participantsWe systematically searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases for studies comparing outcomes of LT patients who received TAC qd versus TAC bid. Outcome measuresResults were reported as odds ratios (ORs) with 95% CIs. ResultsSix studies, which included 5179 LT recipients (TAC qd = 951; TAC bid = 4228) were included in the analysis. The TAC qd group had a low 1-year graft loss rate (OR 0.70 [95% CI 0.54–0.91], P = 0.008) and lower rate of biopsy-proven acute rejection (BPAR) at 90 days (OR 0.46 [95% CI 0.24–0.89], P = 0.02) compared with the TAC bid group. There was no significant difference in 1-year mortality or the incidence of adverse events after LT between the 2 groups. ConclusionsCurrent evidence suggests that TAC qd is safe and effective for LT patients during the first year after transplantation. Longer-term follow-up studies are necessary to determine if TAC qd is safe and effective beyond the first year after LT.

P3.44: Sublingual tacrolimus use in intestinal transplant recipients

Introduction: Therapeutic tacrolimus concentrations are essential to prevent rejection in intestinal transplant patients. Traditional administration of liquid tacrolimus via jejunal tube (JT) immediately post-transplant may require high doses and result in delays in achieving therapeutic concentrations, likely due to decreased enteral bioavailability. Tacrolimus may be administered via the sublingual (SL) route, with passive diffusion of drug across oral mucosa. Administration via the sublingual route avoids enteral metabolism and bypasses the liver first-pass effect, and may result in faster onset of action. There is a paucity of data regarding SL tacrolimus use in intestinal transplant patients. Methods: This was a retrospective, single center review of adult intestinal or multivisceral transplant patients transplanted between 06/2017 and 12/2018 who were converted from JT to SL tacrolimus within the first 30 days after transplant due to subtherapeutic tacrolimus troughs (less than 20 ng/mL). Daily tacrolimus doses, routes, drug levels, and incidence of rejection were recorded. Results: Sixteen patients met inclusion criteria: 12 intestine, 2 multivisceral, 1 intestine+ liver, and 1 intestine+ kidney. Subjects were initiated on JT tacrolimus immediately postoperatively, and were transitioned to SL tacrolimus at an average of 6 ± 3.4 days postoperatively. The mean daily JT dose was 12.2 ± 3.9 mg and the mean JT tacrolimus trough was 9.6 ± 5 .4 ng/mL prior to transition. After changing to SL, the mean daily SL dose was 10.4 mg ± 3.8 and the mean tacrolimus trough was 21.8 ± 3.8 ng/mL. Subjects reached therapeutic levels (greater than 20 ng/mL) 1.9 ± 0.8 days after transition and stayed on SL dosing 13.7 ± 8.1 days during the first month. The conversion ratio of JT to SL tacrolimus was 0.4 ± 0.3. No adverse effects as a result of administering the drug via the sublingual route were noted, and 2 patients were treated for rejection during the first month. Conclusion: The use of sublingual tacrolimus allowed for rapid achievement of target tacrolimus troughs in intestinal transplant patients with the use of lower doses than jejunal tube tacrolimus administration, and may provide a viable option for immunosuppression immediately post-transplant. Limitations include the retrospective nature of the study, as well as conversion of doses prior to reaching steady state. Further prospective dose conversion studies in intestinal transplant patients are warranted.

Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values.

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.

High Tacrolimus Clearance – A Risk Factor for Development of Interstitial Fibrosis and Tubular Atrophy in the Transplanted Kidney

Background Patients showing high tacrolimus clearance eliminate the drug more rapidly, and in order to reach the same trough concentration they need higher daily doses compared to those with low clearance. The high clearance makes them more exposed to transient under-immunosuppression in case of a missed/delayed dose but the higher daily tacrolimus doses cause higher maximum concentrations (Cmax). Both are hypothesized to induce development of interstitial fibrosis and tubular atrophy (IFTA) in the transplanted graft. We wanted to investigate the association between estimated tacrolimus clearance and development of IFTA in the renal transplant during the first year post-engraftment. Methods Data from all patients transplanted between 2009 and 2013 at Oslo University Hospital, Rikshospitalet were included in the analysis. Association between estimated tacrolimus clearance (daily tacrolimus dose [mg]/trough concentration [μg/L]) and development of IFTA, (defined as i+t ≤ 1 and ci+ct ≥ 2) in renal protocol biopsies from 6 weeks to 12 months post-transplantation was investigated. Results In total, 510 patients were treated with tacrolimus and had paired protocol biopsies (6 weeks + 12 months) after transplantation, were included in the analysis. Patients were divided in four groups according to their estimated tacrolimus clearance. There were no differences in biopsy scores between the groups at 6 weeks. The high clearance group developed significantly more IFTA from 6 weeks to 12 months compared to the low clearance group (50% vs 22%, P<0.007). Of the 233 patients without IFTA in the 6-week biopsies a 1-unit increase in tacrolimus clearance was associated with an odds ratio of 1.88 (95% CI; 1.12-3.27) for development of IFTA after adjusting for donor age and deceased donor. Conclusion High tacrolimus clearance was significantly associated with development of IFTA within the first year following renal transplantation. The effect may be explained by higher peak concentrations and/or more severe transient under-immunosuppressive episodes in these patients.

Desensitization and Prevention of Antibody-Mediated Rejection in Vascularized Composite Allotransplantation by Syngeneic Hematopoietic Stem Cell Transplantation.

Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA. Skin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry. Sensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6). In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.

High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation.

Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient subtherapeutic tacrolimus concentrations may induce acute rejection episodes. A retrospective study in all renal transplant patients treated with tacrolimus at our center from 2009 to 2013 was conducted. The association between individually estimated tacrolimus clearance (daily tacrolimus dose [mg]/trough concentration [μg/L]) and biopsy-proven acute rejection (BPAR) the first 90 days posttransplantation was investigated. In total, 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) patients experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not. High estimated clearance is significantly associated with increased risk of BPAR the first 90 days posttransplantation and may predict an increased risk of rejection in the early phase after renal transplantation.

Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet-Kidney Transplantation in Nonhuman Primates.

The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet-kidney transplantation (SIK). Seven MHC-mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti-CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti-inflammatory therapy, including anti-interleukin-6 receptor mAb and anti-tumor necrosis factor-α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long-term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long-term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney-alone transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti-CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients.

Pharmacogenetic-based strategy using de novo tacrolimus once daily after kidney transplantation: prospective pilot study.

The once daily tacrolimus formulation (Tac-OD) has been associated with better patient adherence and low variability in exposure. Patients carrying the CYP3A5*1 allele show accelerated clearance of Tac. Authors prospectively evaluate a simplified strategy for Tac-OD administration. After grafting, 151 patients were divided into four groups and received a daily dose calculated according to CYP3A5 genotypes and unchanged for the first 3 days: CYP3A5*3/*3: 0.20 mg/kg/day, CYP3A5*3/*3: 0.25 mg/kg/day, CYP3A5*1/*3: 0.30 mg/kg/day and CYP3A5*1/*1: 0.35 mg/kg/day. The dose was adaptated on day 4 and remained unchanged a further three days and so on. On day 3, median Cmin fell within the therapeutic range in all study groups. CYP3A5 expressors require significantly higher Tac-OD throughout the follow-up period to achieve a comparable Cmin. This simplified strategy does not hamper treatment efficacy.

The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients.

The aim of this study was to develop a population pharmacokinetic model of tacrolimus in paediatric patients at least 1year after renal transplantation and simulate individualised dosage regimens. We included 54 children with median age of 11.1years (range 3.8-18.4years) with 120 pharmacokinetic profiles performed over 2 to 4h. The pharmacokinetic analysis was performed using the non-linear mixed-effects modelling software (NONMEM(®)). The impact of covariates including concomitant medications, age, the cytochrome P450 (CYP) CYP3A5*3 gene and the adenosine triphosphate binding cassette protein B1 (ABCB1) 3435 C→T gene polymorphism on tacrolimus pharmacokinetics was analysed. The final model was externally validated on an independent dataset and dosing regimens were simulated. A two-compartment model adequately described tacrolimus pharmacokinetics. Apparent oral clearance (CL/F) was associated with weight (allometric scaling) but not age. Children with lower weight and CYP3A5 expressers required higher weight-normalised tacrolimus doses. CL/F was inversely associated with haematocrit (P<0.05) and γ-glutamyl transpeptidase (γGT) (P<0.001) and was increased by 45% in carriers of the CYP3A5*1 allele (P<0.001). CL/F was not associated with concomitant medications. Dose simulations show that a daily tacrolimus dose of 0.2mg/kg generates a pre-dose concentration (C 0) ranging from 5 to 10µg/L depending on the weight and CYP3A5 polymorphism. The median area under the plasma concentration-time curve (AUC) corresponding with a tacrolimus C 0 of 4-8µg/L was 97h·µg/L (interquartile range 80-120). In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A5*1 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A5*1 allele have higher weight-normalised tacrolimus dose requirements.

(647) - Prolonged Administration of Twice Daily Bolus Intravenous Tacrolimus Early after Lung Transplantation

(647) - Prolonged Administration of Twice Daily Bolus Intravenous Tacrolimus Early after Lung Transplantation

Ocular Surface Squamous Cell Carcinoma with Intraorbital Extension in a Patient with Long-Term Immunosuppression

Purpose: To report a case of ocular surface squamous cell carcinoma with intraorbital extension in a patient with renal transplantation and long-term immunosuppressive therapy. Case summary: A 59-year-old Korean male presented with a whitish mass in the medial limbus and conjunctiva of the right eye. The patient had undergone renal transplantation 17 years prior due to lupus nephritis and was on systemic immunosuppression with daily prednisolone (10 mg), tacrolimus (5 mg), and mycophenolate sodium (720 mg). The complete excision of the mass was performed and mitomycin C application and amniotic membrane transplantation on the excised area were combined. Histopathological examination revealed the mass was squamous cell carcinoma. There were no abnormal findings on the orbit computed tomography (CT). The patient was additionally treated with topical interferon alpha 2b 6 months postoperatively. One year later, a mass recurred at the same site in the right eye. The complete excision of the mass, mitomycin C application, cryotherapy, and amniotic membrane transplantation were performed. Orbit CT showed a 1.9 cm-sized intraorbital mass involving the medial rectus of the right eye. The orbital exenteration was performed and the intraorbital mass was histologically proven to be squamous cell carcinoma. Conclusions: Ocular surface squamous neoplasia in patients with renal transplantation and long-term immunosuppressive therapy should be monitored closely for the possibility of orbital invasion. J Korean Ophthalmol Soc 2016;57(3):507-512

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients

PurposeThe once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.MethodsStable liver transplant patients receiving once daily tacrolimus (N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available (N = 49), and demographic factors, CYP3A4*22 and CYP3A5*3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.ResultsPharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4*22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.ConclusionsBoth donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4*22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-015-1963-3) contains supplementary material, which is available to authorized users.

Daily Low-dose Tacrolimus Is a Safe and Effective Immunosuppressive Regimen During Telaprevir-based Triple Therapy for Hepatitis C Virus Recurrence After Liver Transplant

Graft loss because of hepatitis C virus recurrence is a serious problem after liver transplantation (LT), and the response to pegylated interferon (PEG-IFN) and ribavirin (RBV) is poor. The significantly better response rates achieved with telaprevir (TVR)-based triple therapy have led to better graft and patient survival rates, but severe drug interactions may limit the usefulness of this therapy for LT patients. We report our single-center experience with a specially developed protocol that involved administering a low daily dose of tacrolimus (TAC) to a cohort of 17 patients with a recurrence of hepatitis C virus genotype 1 after LT. Patients were treated with TVR, PEG-IFN, and RBV for 12 weeks, followed by 12 or 36 weeks of dual therapy with PEG-IFN and RBV. After TVR administration was initiated, the TAC dosage was skipped until trough levels began to decline; it was then administered at a dose of 0.1 mg once or twice daily. Tacrolimus trough levels and laboratory values were closely monitored during the TVR phase. Deviations in trough levels were avoided, thus preventing any clinically evident renal toxicity related to TAC. In addition, histologic studies performed at the end of therapy showed that no rejection episodes had occurred. All patients tolerated the medication. Sustained virologic response was documented for 10 of 17 patients (58%) 24 weeks after end of treatment. In conclusion, substantial dose reduction and daily administration of low doses of TAC compose a safe and efficient immunosuppressive regimen during TVR-based triple therapy.

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation (Advagraf®) in liver transplant patients

Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4 years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation.The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the identification of additional parameters to be included in future matching algorithms aiming to extend survival of transplanted kidneys and to diminish HLA immunization. Computer simulation studies will reveal the number of patients having a direct benefit from improved matching, the effect on shortening of the waiting list, and the decrease in waiting time.

One Agent-Once a Day: 2 Year Outcomes of a Prospective Randomized Trial of Once Daily (Extended Release) Tacrolimus Maintenance Monotherapy vs Twice Daily (Standard Release) Tacrolimus After Alemtuzumab Induction &amp; Early Steroid Cessation (TAESR Trial). Rejection and Variation in Tacrolimus Levels.

Introduction: The availability of once-daily extended-release tacrolimus (Advagraf), provides the opportunity to develop a one-agent, once-a-day, maintenance immunosuppressive regimen from the well established combination of tacrolimus monotherapy after alemtuzumab induction with early steroid cessation. Methods: We have undertaken a prospective, randomized, controlled trial comparing graft and patient outcomes, and tacrolimus trough level intra-patient variability with once vs twice daily tacrolimus monotherapy (n=52 vs 50 patients). Results: At 2 years post-transplant, patient survival, graft survival, and the incidence of all rejection (biopsy proven acute cellular, and acute and chronic antibody mediated) did not differ significantly between the two arms:Table: No Caption available.Intra-patient variability (coefficient of variation) of tacrolimus levels did not differ significantly between the two groups, although after the first year post-transplant there was a trend to increased variability in the twice daily, standard release group, and decreasing variability in the once daily, extended release group.Figure: No Caption available.Conclusions: Once daily extended release tacrolimus provideds safe and effective maintenance monotherapy after alemtuzumab induction and early steroid cessation, with graft and patient survival, and rejection levels comparable to twice daily, standard release tacrolimus. DISCLOSURES:McLean, A.: Grant/Research Support, Astellas pharma UK.

Tacrolimus dose requirements in African-American and Caucasian kidney transplant recipients on mycophenolate and prednisone.

Racial differences among kidney transplant recipients may impact the total daily tacrolimus dose required to achieve therapeutic tacrolimus concentrations. Previous studies suggest that African Americans require higher doses to achieve similar therapeutic drug concentrations compared with Caucasians. Data were collected on a total of 147 de novo kidney transplant recipients. Tacrolimus total daily dose (TDD) requirements (mg/kg/d) and tacrolimus concentrations were retrospectively reviewed at discharge and at days 30, 60, and 90 after transplant. TDD requirements in African-American and Caucasian patients were 0.14mg/kg/d and 0.11mg/kg/d, respectively (p=0.005), at day 30. TDD requirements at day of hospital discharge and days 60 and 90 following transplant were significantly higher in African-American patients vs. Caucasian patients, with similar tacrolimus concentrations at all time points. This study suggests that when compared to Caucasians, African Americans require significantly higher TDD of tacrolimus to achieve similar tacrolimus concentrations. These findings provide transplant clinicians with a sense of certainty to more rapidly titrate daily tacrolimus doses in African-American patients to achieve therapeutic concentrations.

Co-administration of ketoconazole and tacrolimus to kidney transplant recipients: cost minimization and potential metabolic benefits.

To evaluate the effects of the co-administration of tacrolimus and ketoconazole to a group of kidney transplant recipients, we studied 30 kidney transplant recipients with stable kidney function who were maintained on tacrolimus-based immunosuppression. They were prescribed ketoconazole (100 mg/day) with a concomitant reduction in daily tacrolimus dose to maintain its level within the therapeutic range. The study included 19 males and 11 females with a mean age of 36 ± 12 years. All patients were at least three months post-transplant and had tacrolimus trough levels within the therapeutic range of 5-7 ng/mL. Desired tacrolimus trough levels could be achieved in 29/30 patients after the addition of ketoconazole. This resulted in a significant reduction of the median tacrolimus dose from 5 mg/day (range 3-20 mg/day) at baseline to 2 mg/day (range 1-4 mg/day) (P = 0.00). The median reduction in the tacrolimus dose was 63% (range 50-83%). The median monthly tacrolimus cost dropped from 375 US$ per patient (range 225-1440 US$) to 150 US$ per patient (range 120-300 US$). There were no reported adverse drug effects during the study period. After one year of follow-up, there was a small but significant improvement in the estimated glomerular filtration rate (72 ± 18 versus 78 ± 20 mL/min, P = 0.01) and a significant reduction in serum uric acid levels (7.7 ± 1.7 versus 5.9 ± 0.8 mg/dL, P = 0.003). The co-administration of ketoconazole and tacrolimus to kidney trans-plant recipients is safe and significantly reduces the cost of immunosuppression. In addition, this combination appears to have a beneficial effect on kidney function.