Reduced-exposure Calcineurin Inhibitor Research Articles

Basiliximab as maintenance immunosuppression in heart transplant recipients: A single pediatric center experience.

Pediatric heart transplant recipients are at risk for complications from prolonged exposure to immunosuppressive drugs, pharmacokinetic challenges in maintaining consistent immunosuppression, and medication non-adherence. Basiliximab (BAS), an interleukin-2 receptor antagonist, is used for induction therapy across many pediatric heart transplant centers, but use as maintenance immunosuppression has not been well described. This was a retrospective, single pediatric center cohort study of heart transplant recipients who received BAS for maintenance immunosuppression (defined as >2 monthly doses) from January 1, 2011, to December 31, 2021. Ten patients met study criteria with a median age of 17.5 (5-22)years and median 9.6 (1.2-18.9)years since transplant at time of BAS initiation. The primary indications for BAS use were recurrent rejection (n=4), fluctuating immunosuppression levels (n=3), and renal dysfunction (n=3). A median of 5.5 (3-32) monthly BAS doses were received. Three patients had a rejection event while on BAS. Calcineurin inhibitor exposure was reduced in 70% of patients. Three of the 10 patients were alive at last follow-up. There was one documented infection during BAS use, and no hypersensitivity reactions. Monthly BAS infusions were well tolerated and allowed for reduced calcineurin inhibitor exposure in most patients. Mortality commonly occurred despite BAS use, potentially reflecting the acuity of this patient cohort. BAS can be considered for maintenance immunosuppression in pediatric patients with fluctuating immunosuppressive levels and/or renal dysfunction. More studies are needed to determine long-term outcomes and explore expanded use of BAS in the pediatric heart transplant population.

Reduced calcineurin inhibitor exposure with antibody induction and recurrent hepatocellular carcinoma after liver transplantation

Background Hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT), but post-LT tumor recurrence remains a concern. Early post-LT immunosuppression is suggested to affect recurrence risk. We evaluated the impact on HCC recurrence of an immunosuppression protocol introduced in 2010 with interleukin-2 receptor antibody (IL-2RA) induction and delayed-introduction of reduced-dose tacrolimus with mycophenolate. Methods We included consecutive HCC patients transplanted 2000–2017 in Gothenburg. The impact on HCC recurrence of IL-2RA induction and mean tacrolimus trough concentration during the first 20 post-LT days was analyzed by multivariable Cox regression and propensity score-adjusted analyses. Results The study comprised 235 patients (mean age 57 yrs, men 80%, mean MELD 13, within Milan criteria 57%). The cumulative 5-yr HCC recurrence rate among patients transplanted before and after 2010 were 28.6% and 19.7%, respectively. IL-2RA induction had no independent effect on HCC recurrence. High tacrolimus exposure (mean 20-day tacrolimus concentration ≥8ng/mL) was associated with increased HCC recurrence risk on univariable analysis (HR 2.22, 95% CI 1.23–4.01, p = .008), but was non-significant on multivariable analysis (p = .17). Outside Milan criteria, high tacrolimus exposure was significant for HCC recurrence (HR 3.68, 95% CI 1.34–10.11, p = .012) independently of tumor characteristics and AFP level. This was confirmed on multivariable propensity score-adjusted analysis. Conclusions Reduced early tacrolimus exposure, facilitated by IL-2RA induction, was associated with reduced risk for HCC recurrence among patients outside Milan criteria. Prospective studies are needed to confirm if early tacrolimus-minimization strategies can help reduce HCC recurrence rates and help extend transplant criteria.

Application of the iBox prognostication system as a surrogate endpoint in the TRANSFORM randomised controlled trial: proof-of-concept study

ObjectivesDevelopment of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We applied a validated integrative risk-prognostication system integrative Box (iBox) as a surrogate endpoint to...

Everolimus‐facilitated calcineurin inhibitor reduction in Asian de novo kidney transplant recipients: 2‐year results from the subgroup analysis of the TRANSFORM study

ObjectiveWe analyzed the efficacy and safety of an everolimus with reduced‐exposure calcineurin inhibitor (EVR+rCNI) versus mycophenolic acid with standard‐exposure CNI (MPA+sCNI) regimen in Asian patients from the TRANSFORM study.MethodsIn this 24‐month, open‐label study, de novo kidney transplant recipients (KTxRs) were randomized (1:1) to receive EVR+rCNI or MPA+sCNI, along with induction therapy and corticosteroids.ResultsOf the 2037 patients randomized in the TRANSFORM study, 293 were Asian (EVR+rCNI, N = 136; MPA+sCNI, N = 157). At month 24, EVR+rCNI was noninferior to MPA+sCNI for the binary endpoint of estimated glomerular filtration rate (eGFR) < 50 ml/min/1.73 m2 or treated biopsy‐proven acute rejection (27.0% vs. 29.2%, P = .011 for a noninferiority margin of 10%). Graft loss and death were reported for one patient each in both arms. Mean eGFR was higher in EVR+rCNI versus MPA+sCNI (72.2 vs. 66.3 ml/min/1.73 m2, P = .0414) even after adjusting for donor type and donor age (64.3 vs. 59.3 ml/min/1.73 m2, P = .0582). Overall incidence of adverse events was comparable. BK virus (4.4% vs. 12.1%) and cytomegalovirus (4.4% vs. 13.4%) infections were significantly lower in the EVR+rCNI arm.ConclusionThis subgroup analysis in Asian de novo KTxRs demonstrated that the EVR+rCNI versus MPA+sCNI regimen provides comparable antirejection efficacy, better renal function, and reduced viral infections (NCT01950819).

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients

BackgroundIn 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression.MethodsThis open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is ‘successful transplantation’, defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively.ConclusionsThe OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients.Trial registrationClinicalTrials.gov: NCT03797196, registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study.

After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p=.37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p=.09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.

Wound healing adverse events in kidney transplant recipients receiving everolimus with reduced calcineurin inhibitor exposure or current standard-of-care: insights from the 24-month TRANSFORM study

ABSTRACT Objectives In TRANSFORM, de novo kidney transplant recipients received either everolimus in combination with reduced-exposure calcineurin inhibitor (EVR+rCNI) at standard EVR pre-dose concentrations of 3–8 ng/mL or mycophenolic acid plus standard-exposure CNI (MPA+sCNI). The authors analyzed the incidence of wound healing adverse events (WHAEs) over the 2-year study period 15. Methods Patients were randomized to either EVR+rCNI or MPA+sCNI, both combined with induction therapy and steroids 19. Results The safety population consisted of 2,026 patients (EVR+rCNI: 1,014, MPA+sCNI: 1,012). The proportion of patients with at least 1 WHAE was comparable between EVR+rCNI and MPA+sCNI treatment groups [20.6% vs. 17.3%; risk ratio (RR): 1.19; 95% confidence interval (CI): 0.99, 1.43] at month 24. The numerical difference between EVR+rCNI and MPA+sCNI was mainly caused by an increased proportion of EVR patients with lymphocele and wound dehiscence [7.5% vs. 5.1% (RR: 1.46; 95% CI: 1.04, 2.05) and 3.9% vs. 1.8% (RR: 2.22; 95%CI: 1.28, 3.84), respectively] 20. Conclusion The immediate introduction of EVR+rCNI after kidney transplantation was associated with an overall comparable incidence of WHAEs versus current standard-of-care over the 24-month study period. There was an increased relative risk of experiencing lymphocele and wound dehiscence but the absolute risks were rather low in both groups 21. CT.gov identifier NCT01950819.

COVID-19 in Kidney Transplantation: Outcomes, Immunosuppression Management, and Operational Challenges.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2, has led to the death of hundreds of thousands of people worldwide. If infected, older individuals and those with diabetes, hypertension, cardiovascular disease, and compromised immune systems are at higher risk for unfavorable outcomes. These comorbidities are prevalent in patients with kidney disease, hence the significant burden of COVID-19 on kidney transplant programs. Multiple case series of kidney transplant recipients with COVID-19 have shown increased mortality compared to nontransplant patients. To date, we do not have high-level evidence to inform immunosuppression minimization strategies in infected transplant recipients. Most centers however have adopted early antimetabolite withdrawal in addition to other interventions. This review summarizes the published COVID-19 literature as it relates to outcomes and immunosuppression management in kidney transplant recipients. It also discusses challenges pertaining to pretransplant evaluation and wait-listed patients.

Everolimus for BKV nephropathy in kidney transplant recipients: a prospective, controlled study.

There is no specific therapy for polyoma BK virus nephropathy (BKVN) in kidney transplant recipients, a condition associated with poor outcomes. Everolimus showed promising antiviral effects, but data from prospective studies are limited. Therefore, we converted ten consecutive kidney transplant recipients with biopsy-proven BKVN from standard exposure Calcineurin inhibitors and Mycophenolate to Everolimus and reduced exposure Calcineurin inhibitors. Ten patients not administered Everolimus, on reduced exposure Calcineurin inhibitor and halved MPA doses served as controls. All kidney transplant recipients continued steroid therapy. Each patient underwent kidney graft biopsy, BKV replication by PCR, and de novo DSA determination. During a 3-year follow-up no graft loss occurred in kidney transplant recipients on Everolimus but it was observed in 5/10 controls (P = 0.032). eGFR improved on Everolimus and worsened in controls (between group difference + 25.6ml/min/1.73m2, 95% CI 10.5-40.7, P = 0.002). BKV replication declined in the Everolimus group alone (from 6.4 ± 0.8 to 3.6 ± 1.6 Log 10 genomic copies, P = 0.0001), and we found a significant inverse relationship between eGFR and BKV genomic copy changes (P = 0.022). Average Calcineurin inhibitors trough levels did not differ between the two study groups during follow-up. By multivariable Cox regression analysis, Everolimus treatment resulted the only significant predictor of survival free of a combined endpoint of graft loss and 57% eGFR reduction (P = 0.02). Kidney transplant recipients on Everolimus had a higher survival free of adverse graft outcome (log-rank test, P = 0.009). In conclusion an Everolimus-based immunosuppressive protocol with minimization of Calcineurin inhibitors and antimetabolite discontinuation effectively treated BKVN in kidney transplant recipients.

Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study: Erratum.

Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study: Erratum.

Evidence-based practice: Guidance for using everolimus in combination with low-exposure calcineurin inhibitors as initial immunosuppression in kidney transplant patients.

The mammalian target of rapamycin (mTOR) inhibitor, everolimus, in combination with reduced-exposure calcineurin inhibitor (CNI), has been demonstrated in clinical trials to have comparable efficacy in low-to-moderate immunological risk kidney transplant recipients to the Standard of Care, mycophenolic acid (MPA) in combination with standard-exposure CNI. Current treatment guidelines consider mTOR inhibitors to be a second-line therapy in the majority of cases; however, given that everolimus-based regimens are associated with a reduced rate of viral infections after transplantation, their wider use could have great benefits for kidney transplant patients. In this evidence-based practice guideline, we consider the de novo use of everolimus in kidney transplant recipients. The main outcomes of our consideration of the available evidence are that: 1. Everolimus, in combination with reduced-exposure CNI and low dose steroids, is a suitable regimen for the prophylaxis of kidney transplant rejection in the majority of low-to-moderate immunological risk adult patients, with individualized management; 2. Induction with either basiliximab or rabbit anti-thymocyte globulin is an effective therapy for kidney transplant recipients when initiating an everolimus-based, reduced-exposure CNI regimen; and 3. An individualized approach should be adopted when managing kidney transplant recipients on everolimus-based therapy.

Two-year outcomes in de novo renal transplant recipients receiving everolimus-facilitated calcineurin inhibitor reduction regimen from the TRANSFORM study.

TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR+rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR+rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR)<50mL/min per 1.73m2 was achieved at month 24 (47.9% vs 43.7%; difference=4.2%; 95% confidence interval=-0.3, 8.7; P=.006). Mean eGFR was stable up to month 24 (52.6 vs 54.9mL/min per 1.73m2 ) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR+rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR+rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR+rCNI even in the D+/R- high-risk group (P<.0001). In conclusion, the EVR+rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24months. Clinicaltrials.gov number: NCT01950819.

Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study.

In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (i) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n=71), or to (ii) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n=74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at radomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 post-transplant post-randomization) with superiority of the CNI-free group versus EVR/redCNI : mean 64.1mL/min/1.73m2 versus 52.9mL/min/1.73m2 ; difference +11.3mL/min/1.73m2 (p<0.001). By month 18, estimated GFR had increased by ≥10mL/min/1.732 in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by ≥25 mL/min/1.73m2 in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI versus the CNI-free regimen (p=0.015); 6/15 episodes in CNI-free patients occurred with EVR concentration <5ng/mL. Rates of adverse events and associated discontinuations were comparable EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. This article is protected by copyright. All rights reserved.

Safety of Everolimus With Reduced Calcineurin Inhibitor Exposure in De Novo Kidney Transplants: An Analysis From the Randomized TRANSFORM Study.

The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Renal Function Outcomes in De Novo Kidney Transplant Recipients Receiving Everolimus with Reduced-Exposure Calcineurin Inhibitor versus Mycophenolate with Standard-Exposure Calcineurin Inhibitor

Renal Function Outcomes in De Novo Kidney Transplant Recipients Receiving Everolimus with Reduced-Exposure Calcineurin Inhibitor versus Mycophenolate with Standard-Exposure Calcineurin Inhibitor

MTOR inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now?

Antibody-mediated rejection (AMR) usually starts with generation of donor-specific anti-HLA antibodies (DSAs), arising from a B-cell response to antigen recognition. In vitro and preclinical data demonstrate that mammalian target of rapamycin (mTOR) inhibition attenuates the mTOR-mediated intracellular signaling pathway involved in AMR-related kidney damage. The limited available data from immunological studies in kidney transplant patients, however, have not shown such effects invivo. In terms of clinical immunosuppression, the overriding influence on rates of de novo DSA (dnDSA) or AMR-regardless of the type of regimen-is patient adherence. To date, limited data from patients given mTOR inhibitor therapy with adequate concurrent immunosuppression, such as reduced-exposure calcineurin inhibitor (CNI) therapy, have not shown an adverse effect on the risk of dnDSA or AMR. Early switch to an mTOR inhibitor (<6-12months post-transplant) in a CNI-free regimen, in contrast, can increase the risk of dnDSA, especially if adjunctive therapy is inadequate. Late conversion to CNI-free therapy with mTOR inhibition does not appear to affect the risk of dnDSA. More data, from prospective studies, are required to fully understand that association between use of mTOR inhibitors with different types of concomitant therapy and risk of dnDSA and AMR.

Everolimus immunosuppression for renal protection, reduction of allograft vasculopathy and prevention of allograft rejection in de-novo heart transplant recipients: could we have it all?

De-novo introduction of everolimus (Eve) in heart transplant recipients opens for early reduction of calcineurin inhibitors (CNI) and potential of preserving renal function, attenuate progression of coronary allograft vasculopathy (CAV) and maintain rejection efficacy. The first trials demonstrated adequate rejection prophylaxis and favorable outcomes on CAV, but observed enhanced nephrotoxicity because of insufficient CNI reduction. The SCHEDULE trial compared de-novo Eve with significantly reduced CNI exposure and conversion to CNI-free treatment week 7-11 postheart transplant, with standard CNI immunosuppression. Improved renal function and attenuation of CAV was found among Eve patients, with higher numbers of treated acute rejections observed. With sustained superior renal and CAV related data also after 36 months with the Eve protocol, cardiac function was equally well preserved in both groups. According to the International Society of Heart and Lunge Transplantation registry, mammalian target of rapamycin inhibitor treatment is uncommon during the first postoperative year, with a prevalence of 20% in patients after 5 years. Current evidence suggests a greater benefit from these immunosuppressives if introduced at an earlier timepoint. Immunosuppressive protocols based on Eve treatment in de-novo patients should be further investigated and developed, enabling CNI avoidance before accelerating side-effects lead to irreversible damage.

Optimizing everolimus exposure when combined with calcineurin inhibitors in solid organ transplantation.

The mammalian target of rapamycin (mTOR) inhibitor everolimus is a narrow therapeutic index drug for which optimal exposure levels are essential. The consistent pharmacokinetic profile of everolimus allows trough concentration (C0) measurement to be an appropriate and reliable index for therapeutic drug monitoring (TDM). Exposure-response analyses of data from early fixed-dose trials demonstrated that rates of biopsy-proven acute rejection (BPAR) are significantly higher if everolimus C0 declines below 3 ng/mL, an observation confirmed in subsequent concentration-controlled trials. Evidence for the most favorable upper limit is less clear but with reduced-exposure calcineurin inhibitor (CNI) therapy, an upper limit of 8 ng/mL appears to balance efficacy and safety outcomes. The recommended C0 range is 3-8 ng/mL in kidney, liver and heart transplantation patients, based on LC-MS/MS monitoring in whole blood. Randomized clinical trials based on this target range have demonstrated rates of BPAR comparable to a regimen of mycophenolic acid with standard-exposure CNI. Everolimus exhibits moderate intrapatient pharmacokinetic variability, and it can be challenging to maintain stable concentrations within target range in some individuals. Many factors can influence everolimus exposure for a given dose, including hepatic function, activity of the drug efflux pump P-glycoprotein, the rate of everolimus metabolism, drug-drug interactions (predominantly with CYP3A4 and P-glycoprotein inhibitors, including cyclosporine), intake of fatty food, and patient adherence to the prescribed regimen. Trough concentration levels should be monitored 4-5days after the first dose and after any change in everolimus dose, with additional monitoring in response to any change in concomitant medication or other clinical circumstances which could alter everolimus exposure. Although LC-MS/MS is the gold standard for everolimus monitoring, various immunoassays are widely used due to their relative simplicity and lower cost, and results can show considerable discrepancies with reference methods due to issues such as interassay variability and cross-reactivity. Method standardization will be important in the future to improve the consistency and reproducibility of results between centers. In conclusion, based on an extensive program of clinical trials, the optimal exposure range for everolimus in combination with reduced-exposure CNI therapy has been established and can be achieved in most transplant recipients through careful, planned TDM.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study.

In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.