De Novo Renal Transplant Recipients Research Articles

Outcomes on Allograft Function after 12 Months with Everolimus Plus either Tacrolimus or Cyclosporine Compared to a Standard Tacrolimus-MPA Regimen in De Novo Renal Transplant Recipients

Outcomes on Allograft Function after 12 Months with Everolimus Plus either Tacrolimus or Cyclosporine Compared to a Standard Tacrolimus-MPA Regimen in De Novo Renal Transplant Recipients

Generic Formulation of Mycophenolate Mofetil (Myfenax) in De Novo Renal Transplant Recipients: Results of 12-Month Observation

BackgroundThe aim of this study was to show the preliminary outcomes of transplantation in patients treated with the generic formulation of mycophenolate mofetil (Myfenax, Teva). Materials and MethodsOver the past 4 years, 60 patients received generic mycophenolate mofetil (Myfenax) after renal transplantation at the Gdansk Transplantology Center. During the same time period, another 273 kidney transplantations were performed in our department, and these patients were treated with other formulations of mycophenolate (CellCept [Roche], Myfortic, or mycophenolate mofetil–Apotex) as a part of the immunosuppressive plan. Thirty of the Myfenax patients received a pair of kidneys from the same donor and received original mycophenolate mofetil CellCept with observation for at least 12 months. ResultsThe outcomes of the renal transplantations in both groups (Myfenax vs pair) were good, with satisfactory function of grafts. One case of graft loss was reported in the Myfenax group (renal vein thrombosis, graftectomy 5 days after transplantation). There was no difference in the incidence of acute renal graft rejection in either group. Moderate adverse reactions to immunosuppression were observed in both groups. On the other hand, a comparison between the 60 patients with Myfenax and the 273 other patients with other formulations of mycophenolate revealed no differences in the incidence of acute renal graft rejection, delayed graft function, graft loss, and death. ConclusionsThere were no differences in the incidence of acute renal graft rejection, delayed graft function, graft loss, and death in patients with Myfenax vs original CellCept and other formulations of mycophenolate. To confirm its complete biological and pharmacokinetic equivalence with the reference medicine, long-term, randomized observations carried out on larger renal transplant patients groups are needed.

Effect of Everolimus With Low Dose Tacrolimus Vs Mycophenolate With Standard Tacrolimus Regimen in African-American De Novo Renal Transplant Recipients.

Background: African American (AA) de novo renal transplant recipients (RTxR) are at high risk of graft loss and rejection. This sub-analysis reports data in AA de novo RTxR from a 12M, multicenter randomized, open-label non-inferiority study that evaluated the efficacy and safety of everolimus (EVR)+low-dose tacrolimus (LTac) vs mycophenolate mofetil (MMF)+standard-dose Tac (STac). Methods: In this de novo RTxR (n=613) received EVR (starting at 0.75 mg bid)+LTac or MMF (2 g/day)+STac. All patients (pts) received induction therapy based on immunological risk factors (basiliximab if PRA<20%; or Rabbit anti-thymocyte globulin if PRA ≥20% or high risk) and steroids per local practice. Composite efficacy failure rate at 12M included BPAR, graft loss, death, or lost to follow-up. Renal function (eGFR [MDRD]) was also measured at 12M. Results: Of 613 pts, 144 were AA (EVR+LTac=70, 22.7%; MMF+STac=74, 24.3%). The EVR+LTac (vs MMF+STac) group had fewer living donor recipients (18.6% vs 24.3%) and PRA ≥20% (22.9% vs 35.1%). Moreover, recipients of organs from ECD (11.4% vs 6.8%) and pts with HLA mismatches ≥3 (92.9% vs 85.1%) were more frequent in EVR+LTac vs MMF+STac. Other donor and recipient characteristics were comparable between treatment groups. Composite efficacy failure rates were comparable between treatment groups (Table). Mean eGFR at 12M was also similar (EVR+LTac, 60.8 vs MMF+STac, 60 mL/min/1.73m2). Incidence of any serious adverse event 12M post-transplant was comparable with EVR+LTac vs MMF+STac (52.9%, n=37 vs 60.8%, n=45). The infection rates were lower with EVR+LTac (58.6%) vs MMF+STac (71.6%).Table: No Caption available.Conclusions: Despite the higher risk profile of de novo AA renal transplant recipients in EVR+LTac arm, the efficacy results were similar to MMF+STac. EVR-facilitated Tac minimization also preserved renal function compared to standard therapy and provided lower infection rates. DISCLOSURES:Peddi, V.: Grant/Research Support, Novartis, Astellas. Shaffer, D.: Grant/Research Support, Novartis. Shihab, F.: Other, Novartis, Consultant and Speaker, Astellas, Consultant. McCague, K.: Employee, Novartis Pharmacutical Corporation. Patel, D.: Employee, Novartis Pharmacutical corporation. Mulgaonkar, S.: Grant/Research Support, Novartis, Other, Novartis, Advisor.

Management of the Wound Complications in De Novo Renal Transplant Recipients: US92 12-Month Randomized Study.

Background: In renal transplant recipients (RTxR), reducing CNI exposure with mTOR inhibitor can have a positive impact on renal function (RF). However, the use of higher dose of mTORi-based immunosuppression may be associated with an increased risk for wound complications (WC). Here we report the incidence of WC and management in the US92 study. Methods: In this 12 month (M), multicenter (52 US & Canadian centers), randomized, open-label non-inferiority study, 613 de novo RTxR received everolimus (EVR) (starting at 0.75 mg bid, adjusted to trough level 3-8 ng/ml)+low-dose tacrolimus (LTac; n=309) or mycophenolate mofetil (MMF) (2 g/day)+standard-dose Tac (STac; n=304). All RTxR received induction therapy (basiliximab if PRA<20%; or Rabbit ATG if PRA ≥20%) and steroids per local practice. Primary endpoint was composite efficacy failure rate at 12M (tBPAR, graft loss, death, or lost to follow-up). Incidence of WC with EVR+LTac vs MMF+STac throughout 12M were reported descriptively. Influence of BMI, recipient age, induction agent, and history of diabetes on WC was also analyzed by logistic regression. Results: At 12M, the composite efficacy failure rate with EVR+LTac vs MMF+STac was 24.6%; n=76 vs 20.4%; n=62. In the logistic regression analysis, history of diabetes was the only significant risk factor for WC (OR=1.56, 95% CI [1.04, 2.34], p=0.031) and more recipients had a history of diabetes in EVR+LTac (n=111, 36.3%) vs MMF+STac (n=95, 31.3%). Delayed or impaired transplant incision healing was the most frequently reported WC (Table) and despite the imbalance in baseline characteristics, there was no significant difference between the treatment groups. Similar proportions of patients in both EVR+LTac vs MMF+STac needed surgical repair (7.2% vs 5.6%; p=0.5087) or interventional radiology (4.6% vs 4.3%; p=0.9999).Table: No Caption available.Conclusions: Incidence rate of each WC was not statistically different in EVR+LTac vs MMF+STac. A higher number of patients in EVR+LTac group had history of diabetes that was a significant factor for WC. Management required for WC was similar between the two treatment groups. DISCLOSURES:Shaffer, D.: Grant/Research Support, Novartis. Mulgaonkar, S.: Grant/Research Support, Novartis, Other, Novartis, Advisor. Shihab, F.: Other, Novartis, Consultant and Speaker, Astellas, Consultant. Tomlanovich, S.: Grant/Research Support, Novartis, Genzyme, Genentech, Astellas, Alexion, Pfizer. Patel, D.: Employee, Novartis Pharmacutical Corporation. McCague, K.: Employee, Novartis Pharmacutical Corporation.

Everolimus-Facilitated Tacrolimus Minimization Preserves Renal Function in De Novo Renal Transplant Recipients.

Everolimus-Facilitated Tacrolimus Minimization Preserves Renal Function in De Novo Renal Transplant Recipients.

Influence of Induction Therapy On the Efficacy of Everolimus vs Mycophenolate Based Regimen in De Novo Renal Transplant Recipients.

Introduction: Induction therapy has been shown to lower the risk of acute rejection in renal transplant recipients (RTxR). In this 12-month (M), multicenter (52 US & Canadian centers), randomized, open-label non-inferiority study, we report the outcome by induction therapy (basiliximab vs rabbit anti-thymocyte globulin [rATG]) on the efficacy of everolimus (EVR)+low-dose tacrolimus (LTac) vs mycophenolate mofetil (MMF)+standard-dose Tac (STac) regimen in de novo RTxR. Methods: De novo (n=613) RTxR received EVR (starting dose of 0.75 mg bid)+LTac (n=309) or MMF (2 g/day)+STac (n=304). Induction therapy was based on PRA levels; if PRA<20%, pts received basiliximab (EVR+LTac, n=213; MMF+STac, n=210) and if PRA ≥20% or at high risk (those receiving DCD or ECD) pts received rATG (EVR+LTac, n=96; MMF+STac, n=94). Steroids were administered as per local practice. Composite efficacy failure rate at 12M included tBPAR, graft loss, death, or lost to follow-up. Renal function (eGFR) was estimated at 12M using MDRD formula. Results: HLA mismatches (HLA ≥3) and ECD were more frequent in EVR+LTac group regardless of induction therapy. Induction with rATG resulted in numerically higher composite efficacy failure rates vs basiliximab in both treatment regimens; moreover, the incidence rates of the efficacy endpoints between treatments did not reach the statistical significance (Table). However, in basliliximab induction group, the incidence of tBPAR was significantly higher with EVR+LTac vs MMF+STac (p<0.05); nevertheless, the incidence of graft loss was significantly lower with EVR+LTac vs MMF+STac (p<0.05). At 12M, mean eGFR was comparable in both treatment regimens regardless of induction therapy (Table).Table: No Caption available.Conclusions: Composite efficacy failure rate was higher in the rATG group but this did not reach statistical significance. Regardless of induction therapy the graft and patient survival was high with EVR+LTac (98.7% & 98.1%) and MMF+STac (96.1% & 98.4%) at 1 year. DISCLOSURES:Vincenti, F.: Grant/Research Support, Novartis, Genzyme, Genentech, Astellas, Alexion, Pfizer. Shihab, F.: Other, Novartis, Consultant and Speaker, Astellas, Consultant. McCague, K.: Employee, Novartis Pharmaceuticals Corporation. Patel, D.: Employee, Novartis Pharmaceuticals Corporation. Mulgaonkar, S.: Grant/Research Support, Novartis, Other, Novartis, Advisor. Shaffer, D.: Grant/Research Support, Novartis.

Efficacy and Safety of Everolimus With Low-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Randomized Study.

A multicenter (52 US & Canadian centers), randomized, open-label non-inferiority study assessed efficacy and safety of everolimus (EVR)+low-dose tacrolimus (LTac) vs mycophenolate mofetil (MMF)+standard-dose Tac (STac) regimen in de novo renal transplant recipients (RTxR). RTxR (n=613) started EVR at 0.75 mg bid to maintain trough level of 3-8 ng/mL+LTac (n=309) or MMF (2 g/day)+STac (n=304); with induction therapy, basiliximab (PRA<20%) or rabbit anti-thymocyte globulin (PRA≥20% or high risk) & steroids per local practice. Composite efficacy failure rate at 12M included tBPAR, graft loss, death, or loss to follow-up. Renal function (eGFR) was estimated at 12M using MDRD-4 formula. Of 613 patients (pts), 575 (EVR+LTac 94.8%; MMF+STac 92.8%) completed the study. Donor and recipient characteristics were comparable between treatment arms, except, statistically higher HLA mismatches (HLA≥3; EVR+LTac vs MMF+STac 85.3% vs 78.9% p<0.05), higher baseline diabetes mellitus (36.3% vs 31.3%), deceased donors (55.5% vs 51.4%) & extended criteria donors (ECD; 11.1% vs 8.9%) in EVR arm; and higher current PRA≥20% (13.1% vs 18.1%) in MMF arm. Incidence rates of efficacy endpoints are shown below (Table). At M12, mean eGFR was similar with EVR+LTac & MMF+STac (63.14 vs 63.06 mL/min/1.73m2). Serious adverse event rates through M12 were 50.3% with EVR+LTac vs 46.7% with MMF+STac. Overall infection rates were lower in EVR vs MMF arms (59.2% vs 64.1%). In pts from centers that maintained target EVR levels (excluding pts from centers that have >30% of their EVR levels <3 ng/mL), composite efficacy failure was similar, 22.1% with EVR+LTac and 20.3% with MMF+STac arm [95% CI -5.4, 9.0].Table: No Caption available.In this study, non-inferiority (10% margin) in composite efficacy failure rate for EVR+LTac was not achieved due to higher rate of acute rejection possibly from a higher number of pts with HLA≥3, deceased donors and ECDs in the EVR arm. Despite higher rejection rates, there was significantly lower rate of graft loss in EVR vs MMF arm with similar renal function. It is important to maintain EVR trough levels for a balance between efficacy and safety. DISCLOSURE:Shaffer, D.: Grant/Research Support, Novartis. Peddi, V.: Grant/Research Support, Novartis, Astellas. Shihab, F.: Other, Novartis, Consultant and Speaker, Astellas, Consultant. Yilmaz, S.: Other, Novartis, Service Agreement, Astellas, Service Agreement. McCague, K.: Employee, Novartis Pharmaceuticals Corporation. Patel, D.: Employee, Novartis Pharmaceuticals Corporation. Mulgaonkar, S.: Grant/Research Support, Novartis, Other, Novartis, Advisor.

Reduced Incidence of CMV and BK Virus Infection With Everolimus vs Mycophenolate Based Regimen in De Novo Renal Transplant Recipients.

Reduced Incidence of CMV and BK Virus Infection With Everolimus vs Mycophenolate Based Regimen in De Novo Renal Transplant Recipients.

Pharmacokinetics of Everolimus When Combined With Cyclosporine in Japanese De Novo Renal Transplant Recipients

BackgroundCurrently, there are no published data on pharmacokinetics (PK) of everolimus in combination with cyclosporine in Japanese renal transplant patients. We evaluated the PK of everolimus in Japanese de novo renal transplant patients who received everolimus in combination with cyclosporine. MethodsIn this phase 3, multicenter, randomized, open-label study, patients were randomized (1:1) to 1 of the 2 groups: everolimus 1.5 mg (targeted C0 of 3–8 ng/mL) plus reduced-dose cyclosporine or mycophenolate mofetil 2 g/d plus standard-dose cyclosporine. PK assessments for everolimus were performed on day 28 (month 1) in the PK subpopulation. ResultsA total of 11 patients (7 men), mean age 47.5 ± 11.21 years, were enrolled for PK analysis of everolimus. Starting at 1.5 mg (0.75 mg twice a day), the mean dose over a period of 28 days was 0.705 ± 0.1011 mg. Everolimus mean trough concentration was 4.307 ± 1.2459 ng/mL and mean peak concentration was 13.539 ± 3.5330 ng/mL, which peaked at 1 to 2 hours postdose. The average concentration was 7.558 ± 1.4723 ng/mL, area under the concentration-time curve was 90.70 ± 17.667 ng·h/mL, and peak-trough fluctuation was 122.6%. The PK parameters of everolimus were comparable to those in the earlier phase 3 studies (A2306 and A2307). The mean everolimus trough levels were within the target ranges at all time points ranging from 3.4 to 5.5 ng/mL (everolimus 0.75 mg twice a day, safety population). The majority of patients (>85% from day 7 onward) were maintained within the targeted everolimus trough blood levels (safety population). These data were similar to a non-Japanese study (A2309). ConclusionsThe pharmacokinetic characteristics of everolimus in Japanese de novo renal transplant patients did not differ from those previously observed in non-Japanese patients, hence the same dosage of everolimus may be acceptable in Japanese patients.

Concentration-Controlled Everolimus with Reduced Cyclosporine Concentration in Japanese De Novo Renal Transplant Recipients: Efficacy and Safety Results at 12 Months: Japanese Multicenter Study

Concentration-Controlled Everolimus with Reduced Cyclosporine Concentration in Japanese De Novo Renal Transplant Recipients: Efficacy and Safety Results at 12 Months: Japanese Multicenter Study

Four Year Follow Up of Everolimus and Low Dose Cyclosporine Combination in Denovo Renal Transplant Recipients

Four Year Follow Up of Everolimus and Low Dose Cyclosporine Combination in Denovo Renal Transplant Recipients

Review of Cytomegalovirus Infection Findings With Mammalian Target of Rapamycin Inhibitor-Based Immunosuppressive Therapy in De Novo Renal Transplant Recipients

Cytomegalovirus (CMV) infection and disease are major complications in the renal transplant recipient. The occurrence of CMV is associated with acute rejection, allograft dysfunction, significant end-organ disease, and mortality. Several clinical studies have indicated that the use of certain immunosuppressive drugs can delay the reconstitution of CMV-specific cell-mediated immune responses, thereby leading to uncontrolled CMV replication. Accumulating evidence indicates, however, that the use of the mammalian target of rapamycin (mTOR) inhibitors, sirolimus, and everolimus, may decrease the incidence and severity of CMV infection in renal transplant recipients. The purpose of this article is to review CMV infection data from randomized clinical trials that investigated the use of sirolimus- and everolimus-based treatment regimens in de novo renal transplantation. The mTOR inhibitor clinical trials included were primarily identified using biomedical literature database searches, with additional studies added at the authors' discretion. This review will summarize these studies to discuss whether mTOR inhibitor-based immunosuppressive therapy can reduce the magnitude of CMV-related complications in the de novo renal transplantation setting.

Everolimus plus early tacrolimus minimization: a phase III, randomized, open-label, multicentre trial in renal transplantation

There is increasing interest in tacrolimus-minimization regimens. ASSET was an open-label, randomized, 12-month study of everolimus plus tacrolimus in de-novo renal-transplant recipients. Everolimus trough targets were 3-8 ng/ml throughout the study. Tacrolimus trough targets were 4-7 ng/ml during the first 3 months and 1.5-3 ng/ml (n = 107) or 4-7 ng/ml (n = 117) from Month 4. All patients received basiliximab induction and corticosteroids. The primary objective was to demonstrate superior estimated glomerular filtration rate (eGFR; MDRD-4) at Month 12 in the tacrolimus 1.5-3 ng/ml versus the 4-7 ng/ml group. Secondary endpoints included incidence of biopsy-proven acute rejection (BPAR; Months 4-12) and serious adverse events (SAEs; Months 0-12). Statistical significance was not achieved for the primary endpoint (mean eGFR: 57.1 vs. 51.7 ml/min/1.73 m(2)), potentially due to overlapping of achieved tacrolimus exposure levels (Month 12 mean ± SD, tacrolimus 1.5-3 ng/ml: 3.4 ± 1.4; tacrolimus 4-7 ng/ml: 5.5 ± 2.0 ng/ml). BPAR (months 4-12) and SAE rates were comparable between groups (2.7% vs. 1.1% and 58.7% vs. 51.3%; respectively). Everolimus-facilitated tacrolimus minimization, to levels lower than previously investigated, achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal transplantation over 12 months although statistically superior renal function of the 1.5-3 ng/ml tacrolimus group was not achieved.

Improved Rejection Prophylaxis With an Initially Intensified Dosing Regimen of Enteric-Coated Mycophenolate Sodium in De Novo Renal Transplant Recipients

Approximately half of cyclosporine A-treated renal transplant recipients do not reach sufficient mycophenolic acid (MPA) exposure in the first weeks posttransplantation with standard MPA dosing regimens. Here, we present a prospectively planned meta-analysis of data from two 6-month parallel-run studies that evaluated the effect of an initially intensified versus standard dosing regimen of enteric-coated mycophenolate sodium (EC-MPS). Four hundred forty-one de novo renal transplant recipients were randomized (1:1) to intensified (2 weeks 2880 mg/d; subsequently 4 weeks 2160 mg/d; followed by 1440 mg/d) or standard (1440 mg/d) EC-MPS, with concomitant cyclosporine A treatment and steroids with or without anti-IL-2R induction. Primary endpoint was treatment failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 6 posttransplantation. Treatment failure rates were 17.4% in intensified and 22.4% in standard groups (P=0.110). The incidence of BPAR was 13.8% (intensified) vs. 19.3% (standard; P=0.034). A total of 80.5% (intensified) versus 39.0% (standard) of patients achieved 12 hr MPA-area under the curve more than 30 μg·hr/mL as early as day 3 posttransplant. Renal function, gastrointestinal symptom rating scores, and safety profiles were comparable between treatment groups. The initially intensified EC-MPS dosing regimen was associated with higher MPA exposure, significantly lower rate of BPAR, and comparable safety. However, the intensified regimen did not affect graft function or survival.

Once-a-Day Administration of Everolimus Is Safe in De Novo Renal Transplant Recipients: 1-Year Results of a Pilot Study

Introduction The half-life of everolimus is approximately 28 hours, but everolimus is generally administered twice a day. The aim of this prospective, single-center, exploratory study was to compare the efficacy and safety of a once a day everolimus (OD) with the standard twice a day administration regimen (BID) as immunosuppressive therapy in renal transplantation. Methods Forty-one de novo renal transplant recipients prospectively assigned to OD ( n = 21) or BID ( n = 20) treatment were followed for 1 year. In the OD group, everolimus was orally administered targeting a trough blood level of 2 to 5 ng/mL. In the BID group, everolimus was given twice a day targeting a trough blood level of 3 to 12 ng/mL. All patients also received induction with basiliximab and low-dose calcineurin inhibitor immunosuppression. Results At 1 year follow-up patient and graft survivals were 100%. The intention-to-treat analysis showed similar renal function between the two regimens: serum creatinine values for OD 1.54 ± 0.6 versus BID 1.48 ± 0.53 mg/dL ( P = NS). Also the occurrence of acute rejection episodes was not significantly different: 4.8% in the OD versus 15% in the BID group, ( P = NS). The median trough blood levels were significantly lower among the OD group: OD 4.5 versus BID 7.2 ng/mL ( P < .001). Discussion This study demonstrated that once a day administration of everolimus achieved excellent patient and graft survival and good renal function without an increased incidence of acute rejection episodes.

The Pharmacokinetics of Enteric-Coated Mycophenolate Sodium and Its Gastrointestinal Side Effects in De Novo Renal Transplant Recipients of Hispanic Ethnicity

The aim of the study is to characterize the pharmacokinetics and the gastrointestinal side effect profiles of enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant patients of Hispanic ethnicity. The pharmacokinetic study of EC-MPS was conducted in 11 de novo kidney transplant patients of Hispanic ethnicity. Eight blood samples were obtained after EC-MPS was given at the steady state. Blood concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were measured. The mean age (± standard deviation) was 39.4 (± 12.3) years. The mean daily dose of EC-MPS at the time of the pharmacokinetic study was 1408 ± 108 mg. For MPA and MPAG, the time to peak concentration was 2.5 ± 1.3 hours and 4.6 ± 3.1 hours, respectively; the peak concentration (Cmax) was 19.3 ± 17.2 mg/L and 109.4 ± 49.2 mg/L; and the area under the curve from 6 to 12 hours (AUC6-12) was 32.2 ± 19.3 mg·hr/L and 373.7 ± 235.8 mg·hr/L, respectively, which represents 41.3% and 43.0% of AUC0-12. The AUC0-12 for MPA measured 77.8 ± 53.1 mg·hr/L and for MPAG 869.2 ± 388.8 mg·hr/L. Seven patients (64%) exhibited a second peak at approximately 8.3 hours after the dose at a mean concentration (± standard deviation) of 10.3 ± 7.6 mg/L. The Cmax or AUC of MPA does not correlate with overall Gastrointestinal Symptom Rating Scale scores or subscale scores, but the Cmax of MPAG correlates with indigestion subscale (P = 0.022), diarrhea (P = 0.032), and overall scores (P = 0.028). The AUC of MPAG also correlates with acid reflux (P = 0.024) and indigestion (P = 0.032). The pharmacokinetics of EC-MPS has a high variability in de novo kidney transplant patients of the Hispanic ethnicity, which was similar to other ethnic groups. The MPA exposure expressed by the AUC appears to be higher in Hispanic patients than those reported in other ethnic groups, which may be the result of various factors such as difference of the uridine diphosphate glucuronosyltransferase enzyme genotypes, but gastrointestinal side effects were acceptable and the Cmax or AUC of MPAG showed correlations with gastrointestinal symptoms.

Optimal Everolimus Concentration Is Associated With Risk Reduction for Acute Rejection in De Novo Renal Transplant Recipients

Everolimus (Evl) plus tacrolimus (Tac) in de novo renal transplantation is effective and safe. Whether the concentration of Evl affects efficacy and safety in a Tac-based regimen has not been previously reported. To evaluate whether the concentration of Evl affects biopsy-proven acute rejection (BPAR), renal function, adverse events (AEs); and to assess for pharmacokinetic (PK) interactions. Data were from a prospective, multicenter, open-label, randomized, exploratory 6-month study of 92 renal transplant patients treated de novo with concentration-controlled Evl (target trough levels > or =3 ng/mL) plus low-dose Tac or Evl plus standard-dose Tac; both groups received basiliximab and corticosteroids. Data were pooled across study arms to examine BPAR rates in patients with Evl trough levels less than 3 (n=26), 3 to 8 (n=62), or more than 8 ng/mL (n=4). Groups were stratified by both Evl and Tac trough levels to evaluate glomerular filtration rate and AEs. Evl and Tac PK interactions were evaluated in a subset of 14 patients. Evl trough level of more than or equal to 3 ng/mL was associated with significantly lower rates of BPAR as compared with a trough level of less than 3 ng/mL. Glomerular filtration rate was similar at 6 months for both the low and standard Tac groups. No apparent PK interactions were observed between Evl and Tac. AEs were infrequent and did not seem to be associated with the Evl or Tac level. Evl trough levels > or =3 ng/mL plus Tac are associated with low rates of BPAR without adversely affecting renal function. No evident PK interaction exists between Evl and Tac.

Once Daily Everolimus Is Safe and Effective in De Novo Renal Transplant Recipients: Six-Month Results of a Pilot Study

Introduction The half-life of everolimus is approximately 28 hours, but everolimus is normally administered twice a day. The aim of this prospective, single-center, exploratory study was to compare the efficacy and safety of a once a day (OD) everolimus regimen versus the standard twice a day regimen (BID) for immunosuppressive therapy in renal transplantation. Methods Forty de novo renal transplant recipients prospectively assigned to OD ( n = 21) or BID ( n = 19) were followed for 6 months. In the OD group, everolimus was given orally once a day to target a trough blood level of 2–6 ng/mL. In the BID, group everolimus was given twice a day to target a trough blood level of 3–12 ng/mL. All patients also received induction treatment with basiliximab and low-dose calcineurin inhibitors. Results At 6 months follow-up, patient and graft survivals were 100%; renal function and acute rejection rates were similar between the 2 regimens. Patients in the OD group showed significantly lower cholesterol and triglyceride levels compared with those in the BID group, namely, total cholesterol level, OD 212 ± 54 versus BID 249 ± 59 mg/dL ( P < .05), and serum triglycerides, OD 162 ± 72 versus BID 245 ± 133 mg/dL ( P < .02). Discussion This study showed that OD administration of everolimus provided excellent patient and graft survivals and good renal function without an increased incidence of acute rejection episodes. The lipid profile was significantly better among patients receiving everolimus OD. These findings suggested that everolimus can be safely administered once a day.

Prospective Clinical Trial Comparing Two Immunosuppressive Regimens, Tacrolimus and Mycophenolate Mofetil Versus Everolimus and Low-Dose Cyclosporine, in De Novo Renal Transplant Recipients: Results at 6 Months Follow-up

Objective The aim of this study in renal transplant recipients was to compare a tacrolimus plus mycophenolate mofetil (MMF) immunosuppressive regimen with a combination of low dose of cyclosporine and everolimus. Patients and Methods Sixty consecutive patients were prospectively assigned to receive tacrolimus and MMF (TAC; n = 30) or everolimus and low-dose cyclosporine (EVL; n = 30). Tacrolimus was dosed seeking a trough blood level of 8 to 10 ng/mL by month 3 and 5 to 8 ng/mL thereafter. Everolimus was dosed seeking a trough blood level of 3 to 8 ng/mL by day 7. Cyclosporine was dosed aiming at a C2 blood level of 350 to 700 ng/mL in the first week and 150 to 400 ng/mL thereafter. All patients received induction with basiliximab and maintenance treatment with corticosteroids. Results At 6-months follow-up, patient survival rates (TAC 100% vs EVL 100%) and graft survival rates (TAC 96.7% vs EVL 93.3%) were not significantly different between the groups. Patients in the EVL group showed more acute rejection episodes, but serum creatinine concentrations and creatinine clearances were not significantly different from the TAC group. Among the observed side effects, hypercholesterolemia was significantly higher in the EVL group (total cholesterol: TAC 206 ± 38 vs EVL 250 ± 55 mg/dL; P < .003). Conclusions This study showed that the immunosuppressive association of tacrolimus and MMF produced similar acute rejection episodes, graft survivals, and renal function at 6 months after renal transplantation compared with an immunosuppressive combination of everolimus and low-dose cyclosporine. Dyslipidemia was significantly greater among patients who received everolimus.

Comparing Mycophenolate Mofetil Regimens for de Novo Renal Transplant Recipients: The Fixed-Dose Concentration-Controlled Trial

Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant. Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation. Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration-time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration-time curve and BPAR (0.2572 and 0.5588, respectively). There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.