Everolimus Levels Research Articles

A Narrative Review of Chromatographic Bioanalytical Methods for Quantifying Everolimus in Therapeutic Drug Monitoring Applications

Background: Methods for measuring drug levels in the body are crucial for improving therapeutic drug monitoring (TDM) and personalized medicine. In solid-organ transplants, TDM is essential for the management of immunosuppressive drugs to avoid toxicity and organ rejection. Everolimus is a commonly used immunosuppressant with a small range of safe doses; therefore, it is important to adjust the dose according to each patient's needs. Therefore, reliable methods are required to accurately measure everolimus levels. This study aims to conduct a comprehensive and updated narrative review of chromatographic bioanalytical methods for everolimus quantification. Methods: The authors searched for original research articles published between 2013 and 2023 in Scopus and PubMed and found 295 articles after removing duplicates. Based on their titles and summaries, 30 articles were selected for a detailed review and 25 articles were included in the final analysis. Results: Among the 25 studies, 16 used protein precipitation, mainly with methanol, to prepare the samples, 12 used high-performance liquid chromatography, 11 used ultra-performance liquid chromatography, and 2 used both. Almost all the studies (24 of 25) used tandem mass spectrometry for detection, whereas only 1 used ultraviolet. Conclusions: This comprehensive review of bioanalytical methods for measuring everolimus using chromatography is a useful resource for researchers developing bioanalytical methods for TDM applications. Future trends in everolimus measurement include achieving lower detection limits, owing to the trend of reducing drug doses in therapy by improving sample extraction techniques and using more sensitive methods.

Mammalian Target of Rapamycin Inhibitor Levels Decrease Under Cenobamate Treatment

BackgroundEverolimus therapy has been approved in Tuberous Sclerosis Complex (TSC), for drug-resistant epilepsy as adjunctive therapy. A novel anti-seizure medication is cenobamate, which was approved for adults as adjunctive treatment for focal-onset seizures in drug-resistant epilepsy and is now commonly used in patients with TSC. Drug-drug interactions between cenobamate and mammalian target of rapamycin (mTORi) have not been prospectively evaluated, even though these agents are frequently administered together. MethodsWe performed a retrospective analysis of patients with TSC and compared mTORi drug levels before and after treatment initiation with cenobamate. ResultsWe evaluated 20 patients with clinically diagnosed TSC (male: 55%, female: 45%) with a median current age at last visit of 17.0 years (range: 4-41 years, interquartile range [IQR]: 12.5 years). All patients received mTORi treatment of either everolimus (N = 12, 60%) or sirolimus (N = 8, 40%). Cenobamate treatment led to seizure freedom in 2 patients (10%), reduction of seizures in 9 patients (45%) and no change in seizure frequency in 9 patients (45%). Median maximal cenobamate dose was 200 mg (range: 100-500 mg, IQR: 262.5 mg), for example, 3.2 mg/kg/day (range: 0.8-9.5 mg/kg/day, IQR: 3.2 mg/kg/day). Median everolimus levels decreased significantly after cenobamate initiation from 5.1 ng/ml (range: 1.9-11.6 ng/ml, IQR: 3.8 ng/ml) to 3.4 ng/ml (range: 1-7.9 ng/ml, IQR: 1.7 ng/ml, P = 0.01221). The median sirolimus level did not decrease significantly (P = 0.3828). ConclusionEverolimus levels decreased following cenobamate initiation. This is likely due to CYP3A4 induction of cenobamate. We recommend monitoring of serum plasma levels of mTORi co-administered with cenobamate and adjustment of mTORi doses accordingly.

Safe and Successful Treatment With Pcsk9 Inhibitors in Hypercholesterolemia and Renal Transplantation: A Case Report

Patients with chronic kidney disease (CKD) are more prone to cardiovascular disease (CVD) risks, including CVD-derived sudden death. Additionally, patients with CKD also develop lipid metabolism abnormalities. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) are drugs capable of reducing CVD risk in patients with CKD, but their efficacy is scarcely assessed in transplant patients. Here, we report a case of a 74-year-old man undergoing nephrology follow-up for a cadaver donor kidney transplant. The patient described an atorvastatin allergic reaction after an acute coronary syndrome. Because the patient had a very high risk for CVD, alirocumab was substituted for atorvastatin. The patient showed a well-tolerated and effective response and stable everolimus levels. PCSK9i may be considered a pharmacologic option for treating lipid metabolism disorder and reducing low-density lipoprotein cholesterol in transplant recipients.

Effect of different dose regimens of everolimus in a series of neonates with giant cardiac rhabdomyomas.

Everolimus is a mTOR inhibitor that has been increasingly used in high-risk cardiac rhabdomyomas in recent years. There are questions regarding the optimal dose and duration of therapy with everolimus for cardiac rhabdomyomas. The purpose of this study was to examine retrospectively the dosage-efficacy relationship in seven babies diagnosed with rhabdomyoma treated with different everolimus dose regimens retrospectively. Cardiac rhabdomyoma diagnosis was made in six of seven babies during the prenatal period. Indication of everolimus was an obstruction in six patients and supraventricular tachycardia which is resistant to antiarrhythmic drugs in the remaining one patient. The median age was 8 days (range; 2-105 days) at the time of starting everolimus. It was administered at a dose of 0.25 mg twice a day for two days a week in four patients; 0.1 mg/day in two and 0.4 mg/day in one patient. Serum everolimus level was kept between 5 and 15 ng/ml. All seven cases showed significant regression of cardiac rhabdomyoma within four weeks, and supraventricular tachycardia was controlled in two weeks after everolimus administration.This study demonstrates that everolimus was effective in accelerating regression of the cardiac rhabdomyoma. Dose with 2 × 0,25 mg/day, 2 days a week, seems appropriate. However, lower doses such as 0.1 mg/day are also effective. But dose adjustment should be made according to serum level monitoring.

Early Use of Everolimus as a Third Immunosuppressive Agent for Intestinal Transplantation: A Report of 2 Cases

In patients with intestinal transplantation (ITx), renal function is easily impaired because of long-term parenteral nutrition and side effects of tacrolimus. Everolimus was used in patients with renal insufficiency in our study. We administered everolimus as a third immunosuppressive agent in addition to tacrolimus and steroids for renal sparing in patients who received ITx. We assessed everolimus levels, complications, and renal function. Two patients received everolimus after ITx. Patient 1 was a 13-year-old boy who underwent ITx for an allied disorder of Hirschsprung's disease. After induction therapy with rabbit antithymocyte globulin, maintenance therapy consisted of tacrolimus and steroids. Everolimus was introduced 3 months after ITx for renal sparing. Seven months later, the patient required partial intestinal graft resection owing to bowel obstruction. Everolimus was suspended for only 2 weeks. Four years after ITx, the trough level of tacrolimus was maintained at 3 to 5 ng/mL. The trough level of everolimus was maintained at 3 to 5 ng/mL. Patient 2 was a 32-year-old man who underwent deceased ITx for short gut syndrome. Induction and maintenance immunosuppression was the same as for patient 1. Everolimus was introduced 1 month after surgery. Two years after ITx, trough levels of tacrolimus and everolimus were the same as in patient 1. No rejection was observed in either patient, and renal function was well maintained. We observed no side effects caused by everolimus. Everolimus could be used safely and effectively after ITx. Early use of everolimus after ITx did not affect wound healing.

Everolimus for the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy After Heart Transplantation (RADTAC Study)

ObjectivesThis study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BackgroundCalcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. MethodsIn this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (ΔLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. ResultsForty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 ± 3.5 μg/l vs. 8.6 ± 2.8 μg/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 ± 1.7 μg/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (ΔLVM = −13.0 ± 16.8 g vs. 2.1 ± 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Δ circumferential strain = −2.9 ± 2.8 vs. 2.1 ± 2.3; p < 0.001; ΔT1 mapping values = −32.7 ± 51.3 ms vs. 26.3 ± 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Δ mean arterial pressure = 4.2 ± 18.8 mm Hg vs. 2.8 ± 13.8 mm Hg; p = 0.77), renal function (Δ creatinine = 3.1 ± 19.9 μmol/l vs. 9 ± 21.8 μmol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. ConclusionsThe combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

P1762THE EFFECT OF IMMUNOSUPPRESSIVE THERAPY ON THE CLINICAL FOLLOW-UP OF BK VIRUS IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims BK virus nephropathy occurs in up to 10% of kidney transplant recipients and can result in graft loss. The reactivation of BK virus is largely asymptomatic, and routine surveillance especially in the first 12-24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and antiviral treatment in the early stages may be effective in stopping BK virus replication. This study is designed to investigate the effect of management in immunosuppressive therapy on BK virus titers and graft functions in our kidney transplant group. Method A total of 370 kidney transplant recipients between the ages of 18-69 years and receiving a triple immunosuppressive therapy (Tacrolimus+Mycophenoloic Acid+Prednisolone) were included in the study. Demographic characteristics, BK virus titers, serum creatinine and immunosuppressive drug (Tacrolimus, Everolimus) levels were measured at regular intervals in the first 24 months. Among these patients 43 of them were found to have BK virus positivity. At the time of the detection of BK virus positivity, patients were divided into three groups regarding the change in the immunosuppressive protocols: Group I: Tacrolimus + Everolimus + Prednisolone, Group II: Everolimus + Prednisolone, Group III: Tacrolimus + Prednisolone. BK virus titers and graft functions of all three groups were compared with each other. SPSS 15 for Windows was used for statistical analysis. Results The mean age of the patients was 45.3 years, and the mean duration of transplantation was 16.3 months at the time of the BK virus positivity. During the follow-up, mean Tacrolimus levels were found to be in their highest value (14.1 ng/mL) in the posttransplant three months while BK virus titer reached the highest value (1.1x106 copies/ml) in the posttransplant seven to nine months. Increased creatinine values two months after BK virus positivity were strongly correlated (p = 0.02, p = 0.008, p = 0.05, p = 0.002 at 6th, 9th, 12th and 24th months, respectively). A significant decrease in BK virus titers was observed in all three groups due to reductions in immunosuppressive treatment protocol (p = 0.005, p = 0.003, p = 0.028, in groups I, II, III respectively). Conclusion Our study favors the benefits of the prospective screening for BK virus to identify early viral replication, permit intervention, and prevent progression to nephropathy or allograft loss. The best studied treatment for BK viremia and nephropathy is careful reduction of immunosuppression

Effects of Broad Spectrum Antibiotics on Measurement of Immunosuppressant Drugs

Antibiotics used parenterally can affect blood drug level measurements, as measured in diagnostic tests. To investigate the effect of six different antibiotics commonly used in intensive care units on tacrolimus, sirolimus, everolimus and cyclosporin A levels measured by mass spectrometry. Ampicillin + sulbactam (AB1, IV, 1 g), imipenem + cilastatin sodium (AB2, IV, 500 mg), piperacillin + tazobactam (AB3, 4.5 g, IV), ertapenem (AB4, IV, 1 g), meropenem trihydrate (AB5, 500 mg, IV) and ceftriaxone (AB6, 1 g, IV) antibiotics were used for the interference assay. Measurements were performed on the Shimadzu 8045 (Japan) LC-MS/MS instrument. Bias values were calculated. The least affected immunosuppressant was cyclosporine A (between -6.88% and 3.40%). The most affected were everolimus and sirolimus. Ertapenem caused negative interference on the level of everolimus at the rate of -27.34% and sirolimus at the rate of -26.79%. Piperacillin + tazobactam and imipenem + cilastatin sodium caused positive interferences on sirolimus at the rate of 24.24% and 22.73%, respectively. Ampicillin + sulbactam, meropenem trihydrate and ceftriaxone affected the sirolimus levels at lower rates (-4.49%, 5.93% and 9.86%). Everolimus levels deviated at the rate of -11.21% to -16.99% due to imipenem + cilastatin sodium, meropenem trihydrate and ceftriaxone. This study demonstrated the potential of antibiotic use affecting immunosuppressant levels. Antibiotic interference, especially in transplant patients, may cause erroneous immunosuppression, increasing the likelihood of rejection.

Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249).

Background:S0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.Methods:Patients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.Results:A total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0–12.9, 12.9–22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p = 0.02 and OR = 2.63; p = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p = 0.01 and OR = 2.90; p = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p = 0.05).Conclusions:We identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity.

Optimal dose of everolimus administered with tacrolimus in living donor kidney transplantation

Everolimus (EVR) is often administered with cyclosporine A (CsA), according to an established protocol. Although the administration protocol of EVR with tacrolimus (TAC) has not been established, it has been clinically demonstrated that a higher dose of EVR is necessary when used in combination with TAC than with CsA. In this study, we aimed to determine the optimal dose of EVR administered with TAC to maintain a similar EVR level in the blood to that observed when EVR is administered with CsA. Between June 2009 and January 2016, 22 patients who underwent living donor kidney transplantation were enrolled in this study. Among them, 12 patients were administered steroids, basiliximab, CsA, and EVR (CsA + EVR group) and 10 were administered steroids, basiliximab, TAC, and EVR (TAC + EVR group). Blood samples were collected at different time points from patients in both CsA + EVR and TAC + EVR groups, after drug administration. The trough EVR level in both groups was maintained within 3–8 ng/mL during the perioperative period. The optimal EVR doses for both groups were estimated by using a population pharmacokinetic analysis. Overall, the optimal dose of EVR for the TAC + EVR group was 3.59-fold higher than that for the CsA + EVR group to maintain a similar trough level to that of the latter group. Thus, administration of a higher EVR dose is recommended when provided in combination with TAC than with CsA to prevent adverse events caused by under immunosuppression, that could lead to acute kidney rejection.

False Immunosuppressant Measurement by LC-MS/MS Method Due to Radiopaque Agents.

Although liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is preferred as a reliable method, some molecules in the blood matrix may lead to false positive or false negative results. False positive or negative results show the direction of the deviation rate from the target value. The aim of this study was to investigate the effect of seven different radiopaque agents on four immunosuppressant drugs. Every agent coded with RM1 to RM7 was added to control materials containing tacrolimus, everolimus, sirolimus, and cyclosporine A drugs. Measurements were performed using an LC-MS/MS instrument. Bias values were calculated to detect the deviation rates. All RMs led to false negative results in the tacrolimus and cyclosporine A levels at a rate of -19.77% (95% CI, -27.16 to 12.52) to -44.45% (95% CI, -49.20 to -39.69). The smallest deviations were seen in the everolimus levels with the administration of RM6 (gadodiamide) and in the sirolimus levels with RM1 (gadobutrol) at the rates of 4.04% (95% CI, -11.36 to -3.17) and 2.11% (95% CI, -7.18 to 7.11), respectively. The most affected drug by RM4 (gadopentetate dimeglumine salt) was sirolimus at the rate of 114.01% (95% CI, 97.31 - 130.76). RM5 (gadodiamide) interfered cyclosporine A at the most. The highest deviations were observed with the administration of RM3 (iohexol) in the everolimus and sirolimus levels at the rates of 153.72% (95% CI, 142.44 to 164.78) and 171.41% (95% CI, 157.91 to 184.97), respectively. Radiopaque agents interfered the measurement of immunosuppressant drugs. Especially, everolimus and sirolimus levels were affected due to using iohexol. The choice of gadodiamide or ioversol is important to reduce the risk of interference for everolimus measurement. The blood samples should be obtained for measurement of drug levels before contrast-enhanced imaging.

Mechanistic analyses in kidney transplant recipients prospectively randomized to two steroid free regimen-Low dose Tacrolimus with Everolimus versus standard dose Tacrolimus with Mycophenolate Mofetil.

Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively randomized to (steroid free) low dose Tacrolimus (TAC) and EVR or standard dose TAC and Mycophenolate (MMF) after Alemtuzumab induction. Baseline characteristics were statistically similar. EVR levels were maintained at 3–8 ng/ml. TAC levels were 4.5±1.9 and 6.4±1.5 ng/ml in the TAC+EVR and TAC+MMF group respectively. Follow up was 14±4 and 17±5 months respectively and included protocol kidney biopsies at 3 and 12 months post-transplantation. Rejection-rate was lower in the TAC+EVR group. However patient and overall graft survival, eGFR and incidence of adverse events were similar. TAC+EVR induced expansion of CD4+CD25hiFoxp3+ regulatory T cells as early as 3 months and expansion of IFN-γ+CD4+CD25hiFoxp3+ regulatory T cells at 12 months post-transplant. Gene expression profile showed a trend toward decreased inflammation, angiogenesis and connective tissue growth in the TAC+EVR Group. Thus, greater tolerogenic mechanisms were found to be operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF. However, further studies with longer follow up and evaluating impact on T regulatory cells are warranted.

Everolimus in the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy in Heart Transplantation (RAD-TAC Study)

Purpose To determine whether low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus without everolimus safely attenuates left ventricular hypertrophy after heart transplantation Methods In this prospective study, orthotopic heart transplant (OHT) transplant recipients were randomized at 12 weeks post-transplant to a combination of everolimus, tacrolimus (low dose), mycophenolate and prednisolone (RAD-TAC group) OR tacrolimus (normal dose) mycophenolate and prednisolone (TAC group). Left ventricular mass (LVM), mass index (LVMi), function and fibrosis markers (T1 mapping) were assessed by Cardiac MRI (CMR) at baseline and at 52 weeks post-transplant Results Forty patients were randomized. Patient characteristics, including LVMi, age and gender were evenly matched between groups at baseline. Patients in the RAD-TAC group had significantly lower tacrolimus levels (5.5 (1.5) ug/L vs. 8. 3 (3.1) ug/L, mean (SD); p=0.03). The mean everolimus level was 6.8 (1.8) ug/L. LV Mass in the RAD-TAC group significantly reduced over the 40-week study period; in contrast, LV Mass in the TAC group increased (LV Mass change -11.1g (18.3) vs. +0.4g (6.3); p=0.001, LVMi change -6.1g/m2 (8.8) vs.+1.4g/m2 (5.8); p=0.001). Interstitial fibrosis (by CMR T1 mapping) in the RAD-TAC group significantly reduced over the 40-week period; in contrast, interstitial fibrosis in the TAC group increased (fibrosis change -31 (51) ms vs. +33 (-94) ms; p=0.002). No significant differences were observed in measures of myocardial function, significant rejection episodes, hypertension (systolic BP 131 (9.2) mmHg vs. 132 (8.5) mmHg; p=0.51) or serious adverse events between groups Conclusion Low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus safely attenuates left ventricular hypertrophy after heart transplantation. The reduction in CMR-determined fibrosis also provides insights into a potential mechanistic role of everolimus in the pathophysiology of cardiac hypertrophy after transplantation. To determine whether low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus without everolimus safely attenuates left ventricular hypertrophy after heart transplantation In this prospective study, orthotopic heart transplant (OHT) transplant recipients were randomized at 12 weeks post-transplant to a combination of everolimus, tacrolimus (low dose), mycophenolate and prednisolone (RAD-TAC group) OR tacrolimus (normal dose) mycophenolate and prednisolone (TAC group). Left ventricular mass (LVM), mass index (LVMi), function and fibrosis markers (T1 mapping) were assessed by Cardiac MRI (CMR) at baseline and at 52 weeks post-transplant Forty patients were randomized. Patient characteristics, including LVMi, age and gender were evenly matched between groups at baseline. Patients in the RAD-TAC group had significantly lower tacrolimus levels (5.5 (1.5) ug/L vs. 8. 3 (3.1) ug/L, mean (SD); p=0.03). The mean everolimus level was 6.8 (1.8) ug/L. LV Mass in the RAD-TAC group significantly reduced over the 40-week study period; in contrast, LV Mass in the TAC group increased (LV Mass change -11.1g (18.3) vs. +0.4g (6.3); p=0.001, LVMi change -6.1g/m2 (8.8) vs.+1.4g/m2 (5.8); p=0.001). Interstitial fibrosis (by CMR T1 mapping) in the RAD-TAC group significantly reduced over the 40-week period; in contrast, interstitial fibrosis in the TAC group increased (fibrosis change -31 (51) ms vs. +33 (-94) ms; p=0.002). No significant differences were observed in measures of myocardial function, significant rejection episodes, hypertension (systolic BP 131 (9.2) mmHg vs. 132 (8.5) mmHg; p=0.51) or serious adverse events between groups Low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus safely attenuates left ventricular hypertrophy after heart transplantation. The reduction in CMR-determined fibrosis also provides insights into a potential mechanistic role of everolimus in the pathophysiology of cardiac hypertrophy after transplantation.

Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study

BackgroundEverolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.MethodsPatients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated.ResultsThe median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1–28.0) ng/mL and 14.8 (6.4–58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26–288) and 235 days (95% CI, 28–291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436).ConclusionsThis study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.

Life-Threatening Everolimus-Associated Pneumonitis: A Case Report and a Review of the Literature

IntroductionNoninfective pneumonitis is a class-related effect within mammalian target of rapamycin (mTOR) inhibitors, including everolimus, and can occasionally be severe. Case ReportA 62-year-old man, medicated with everolimus due to a heart transplantation 17 years previously and with chronic kidney disease, was admitted to the intensive care unit (ICU) with acute respiratory failure, cardiovascular shock, and impaired renal function requiring dialysis. Computed tomography (CT) scan revealed right upper lobe consolidation. Extensive microbiological workup, autoimmune testing, and cytology were negative and echocardiography showed preserved heart function. Everolimus levels were normal (5.7–6.1 ng/mL) and the drug was suspended at day 9. The patient was difficult to ventilate and responded poorly to broad-spectrum antibiotic and antifungal therapy. On day 25, CT scan and bronchoscopy revealed left-sided alveolar hemorrhage, and corticosteroid pulses were performed. The patient gradually improved. After discharge and 6 months of follow-up, clinical recovery was complete and chest imaging substantially improved. DiscussionPneumonitis occurs in up to 4.3% of transplant recipients using everolimus for immunosuppression. Despite usually presenting as a mild and self-limited disease, severe cases have been described. Alveolar hemorrhage can occur and is associated with poor outcome. Everolimus levels do not seem to accurately predict toxicity. Corticosteroid therapy has been used with success in severe disease. We review the pathophysiological, clinical, and management-related aspects of this entity with emphasis on its potential severity. ConclusionOur case was a rare occurrence of severe life-threatening pulmonary disease related to everolimus. Awareness of the potential severity of this entity is important for the management of patients using mTOR inhibitors.

Everolimus-Induced Pneumonitis in a Liver Transplant Patient: An Emphasis on Management

Introduction: Everolimus is an orally active mTOR inhibitor immunosuppressive agent used in solid organ transplant recipients. It has been associated with pneumonitis in 8 to 14 percent of patients. We present a case with severe everolimus induced pneumonitis managed with intravenous steroids and permanent discontinuation of everolimus. Case presentation: A 55 year-old male who had a liver transplantation in 2013 for cirrhosis due to non-alcoholic steatohepatitis on immunosuppression with everolimus 1 mg in the morning & 0.75 mg in the evening, and tacrolimus 0.5 mg daily. He was admitted with gradual onset acute hypoxic respiratory failure. His everolimus level was 9.6 and tacrolimus level was 2. All cultures were negative. Chest X-ray showed diffuse bilateral moderate ground glass appearance. Computed tomography chest showed diffuse bilateral symmetrical patchy airspace opacification of the lungs. He was treated with broad-spectrum antibiotics but had increasing oxygen requirement to 15L. He had cardiac ejection fraction of 40-50% but did not respond to bipap and aggressive diuresis. Everolimus plasma levels were within the therapeutic range throughout the whole period (5-12 ng/ml). A diagnosis of everolimus pneumotoxicity was made, his everolimus was stopped and he was started on solumedrol 40 mg intravenous (IV) daily. There was rapid improvement in breathing and decrease in oxygen requirement to room air within two days. He was discharged on Prednisone 40 mg daily for 4 weeks, tapered by 5 mg weekly. Discussion: The exact pathogenesis of the everolimus induced lung toxicity includes possible interaction with the Signal transducer and activator of transcription (STAT1) transcription factor. Patients with severe pneumonitis had radiologic evidence of pneumonitis or baseline interstitial lung disease before drug administration. The most common symptoms are dyspnea, cough, fatigue, and fever. The most common radiographic features are focal areas of consolidation at the lung bases or ground glass opacities. Findings on bronchoalveolar lavage include lymphocytosis and increased eosinophil count. Transbronchial lung biopsies reveal interstitial lymphocytic inflammation. The clinical suspicion needs to be high in every patient treated with a mTOR inhibitor presenting with new onset of pulmonary symptoms. Management approach is suggested in Table 1.Table: Table. Management of everolimus induced pneumonitis

Everolimus (EVE) exposure as a predictor of toxicity (Tox) in renal cell cancer (RCC) patients (Pts) in the adjuvant setting: Results of a pharmacokinetic analysis for SWOG S0931 (EVEREST), a phase III study (NCT01120249).

4566 Background: S0931 is assessing recurrence-free survival in RCC pts randomized to receive EVE versus placebo for one year following nephrectomy. To date, there has been a higher than expected dropout rate due to bothersome tox. Previous reports have shown an association between EVE trough levels and both tox and disease response in RCC pts. Therefore, we have assessed EVE trough levels to evaluate the relationship between measured exposure and probability of tox. This analysis has been approved by the DSMC. Methods: Patients received 10 mg daily EVE or placebo for nine 6-week cycles. Pre-dose whole blood samples collected pre-cycle 2 and pre-cycle 3 were analyzed for EVE. Pts with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. When both trough levels were available, results were averaged. Pts were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the following adverse event outcomes using EVE trough as a predictor; any grade 3+ tox, grade 2+ triglycerides, grade 2+ hyperglycemia, grade 2+ oral mucositis, grade 2+ rash, and premature stopping of EVE. Hazard and odds ratios were adjusted for age, BMI and performance status. Results: This study reached its accrual goal and closed on 9/15/2016 with 1545 (775 EVE) randomized patients. A total of 386 pts are included in this preliminary analysis. Median EVE trough was 12.8 ng/mL (range 3.1, 75.6) per 10 mg dose. Event rates for tox were: any grade 3+ tox = 46%, grade 2+ triglycerides = 33%, grade 2+ hyperglycemia = 15%, grade 2+ oral mucositis = 34%, grade 2+ rash = 15%, and premature stopping of EVE = 40%. The risk of grade 2+ triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.95; p = 0.001 and OR = 3.48; p &lt; 0.001). The risk of grade 2+ rash was increased in Q2 and Q4 vs Q1 (OR = 2.95; p = 0.02 and OR = 3.20; p = 0.01). There was also a trend towards an increased risk of any grade 3+ tox in Q3 vs Q1 (OR = 1.72; p = 0.07). Conclusions: This analysis has identified significant associations between EVE exposure and the probability of tox. EVE analysis is ongoing and the final results will be presented. Clinical trial information: NCT01120249.

Therapeutic Potential of Everolimus on Core Autism Symptoms and Increasing Serum Ceruloplasmin and Transferrin Levels in a Pubescent Boy with Tuberous Sclerosis

Background: The neuropsychiatric clinical manifestations of tuberous sclerosis complex (TSC) include social and behavioral impairment, similar to the core symptoms of autism spectrum disorder (ASD), as well as subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs). Case report: The present study examined the clinical effects of 24 weeks of therapy with the mTOR inhibitor everolimus on the social and behavioral symptoms that are similar to the core ASD symptoms and neurobiological mechanisms underlying the effects of everolimus in an 11-year-old boy with TSC. After the initial physical and psychological screening and Magnetic resonance imaging (MRI) examinations, the patient received 4.4 mg/day everolimus for 24 weeks. To study neurobiological mechanism, we examined the relationship between the efficacy of everolimus and serum levels of superoxide dismutase (SOD) and the copper- and iron-binding antioxidants ceruloplasmin (Cp) and transferrin (Tf). Results MRI results revealed a Subependymal giant cell astrocytoma (SEGA) located at the foramen of Monro and a renal angiomyolipoma (AML) on the patient’s kidney. Everolimus remarkably improved the patient’s social and behavioral impairments over the course of the 24-week treatment without apparent reduction in the size of the SEGA and AML. Serum Cp and Tf levels were gradually increased in response to the improvement in symptoms. Conclusion: As everolimus increased antioxidant capacity and elevated serum VEGF levels, this study firstly revealed that increased antioxidant activity related to copper and iron may contribute to the remarkable improvement in the core social and behavioral ASD symptoms caused by 24-week everolimus treatment.

Outcomes of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: A single institution experience in Japan.

To evaluate the efficacy and toxicity profiles of everolimus in Japanese patients with renal angiomyolipoma associated with tuberous sclerosis complex. Patients with a 4-cm or larger angiomyolipoma meeting the diagnostic criteria of tuberous sclerosis complex were selected as participants of our investigation. In each case, we assessed tuberous sclerosis complex-associated symptoms, the treatment effect and adverse events. The treatment effect was evaluated by measuring the tumor volume reduction rate using abdominal computed tomography or magneitc resonance imaging. Adverse events were investigated using CTCAE v4.0-JCOG. The dose of everolimus was set at 10 mg once a day for adults. For childhood angiomyolipoma, everolimus administration was initiated at a dose of 5 mg once a day. Blood everolimus level was measured, and the dose was adjusted to maintain this within a range of 5-15 ng/mL. The angiomyolipoma volume decreased in 46 of 47 cases, and the mean reduction rate for all cases was 60% in 12 months. The angiomyolipoma volume markedly decreased in the first 3 months, and the size leveled off after 6 months. The main adverse events related to everolimus treatment were stomatitis (91%) and irregular menstruation (65%). Grade 3 or severer adverse events were noted in three cases (6%). All patients developed some adverse events in the first 6 months. The incidence markedly decreased to 40-50% after 13 months. The tumor volume-reducing effect of everolimus in a Japanese population was equivalent to or higher than that in Western populations. A wide variety of everolimus treatment-related adverse events can be observed, but most cases are very mild. Special attention should be given to stomatitis, irregular menstruation and interstitial lung disease as adverse events.

Functional and histological improvement after everolimus rescue of chronic allograft dysfunction in renal transplant recipients.

BackgroundWe tested the strategy of mTOR inhibitors with calcineurin inhibitor minimization in renal transplant recipients with known chronic allograft dysfunction.MethodsIn this open-label, single-arm study, renal transplant patients were recruited after biopsy-confirmed chronic allograft dysfunction in the absence of acute rejection episode within 2 months, with proteinuria <0.8 g/day, and serum creatinine <220 μmol/L or estimated glomerular filtration rate >40 mL/min/1.73 m2. They were converted to everolimus (aiming for trough everolimus level 3–8 ng/mL) with cyclosporine minimization, to assess the effect on renal function, rate of glomerular filtration rate decline, and longitudinal transplant biopsy at 12 months.ResultsSeventeen Chinese patients (median transplant duration, 4.2 years) were recruited; no patients discontinued study medication. The mean slope of the glomerular filtration rate over time was −4.31±6.65 mL/min/1.73 m2 per year in the year before everolimus, as compared with 1.29±5.84 mL/min/1.73 m2 per year in the 12 months of everolimus therapy, a difference of 5.61 mL/min/1.73 m2 per year (95% confidence interval [CI], 0.40–10.8) favoring everolimus therapy (P=0.036). Serial renal biopsy histology showed significant decrease of tubular atrophy (15.7%±11.3% versus 7.1%±7.3%, P=0.005) and interstitial fibrosis (14.8%±11.5% versus 7.2%±8.2%, P=0.013). Intrarenal expression of TGF-β1 mRNA showed a nonsignificant decrease after everolimus treatment.ConclusionIn renal transplant recipients with biopsy-confirmed chronic allograft dysfunction, we found a significant beneficial effect of everolimus rescue therapy and calcineurin inhibitor minimization strategy on the improvement of glomerular filtration rate decline rate. In secondary analysis, everolimus was shown to slow down the disease progression by reducing the tubular atrophy and interstitial fibrosis scoring.