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Everett E. Vokes - One of the best experts on this subject based on the ideXlab platform.

  • Everolimus exhibits efficacy as a radiosensitizer in a model of non small cell lung cancer
    Oncology Reports, 2012
    Co-Authors: Helena J. Mauceri, Harold G. Sutton, Thomas E. Darga, Masha Kocherginsky, Joel Kochanski, Ralph R. Weichselbaum, Everett E. Vokes
    Abstract:

    Signaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition can restore sensitivity to DNA damaging agents such as cisplatin. The rapamycin derivative Everolimus exhibits antitumor activity and is approved for patients with renal cell cancer. Clinically, Everolimus has also been evaluated in patients with advanced non-small cell lung cancer (NSCLC) that were refractory to chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors. We tested the effects of combined treatment with Everolimus (RAD001) and fractionated radiation using a xenograft model of human NSCLC (A549 cells). In growth studies, mean tumor volume was reduced in the Everolimus plus 30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone (p=0015), or Everolimus alone (p<0.001, ANOVA). Everolimus (20 nM) significantly reduced protein levels of the mTOR downstream effector p70-S6K compared with radiation and vehicle (p=0.05, ANOVA) and significantly suppressed phospho-p70-S6K levels compared with all other treatments (p<0.001, ANOVA). We also evaluated Everolimus and radiation effects on gene expression in A549 cells. Everolimus ± 5 Gy suppressed endothelin 1 and lactate dehydrogenase expression and increased VEGFA, p21, hypoxia-inducible factor-1α and SLC2A1 (facilitated glucose transporter 1). mTOR mRNA levels were unaffected while TNF-α levels were increased with Everolimus + 5 Gy compared to either treatment alone. These findings suggest that Everolimus increases the antitumor activity of radiation. Clinical trials combining Everolimus with fractionated radiation in patients with NSCLC are warranted.

  • Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer
    Oncology Reports, 2012
    Co-Authors: Helena J. Mauceri, Harold G. Sutton, Thomas E. Darga, Masha Kocherginsky, Joel Kochanski, Ralph R. Weichselbaum, Everett E. Vokes
    Abstract:

    : Signaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition can restore sensitivity to DNA damaging agents such as cisplatin. The rapamycin derivative Everolimus exhibits antitumor activity and is approved for patients with renal cell cancer. Clinically, Everolimus has also been evaluated in patients with advanced non-small cell lung cancer (NSCLC) that were refractory to chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors. We tested the effects of combined treatment with Everolimus (RAD001) and fractionated radiation using a xenograft model of human NSCLC (A549 cells). In growth studies, mean tumor volume was reduced in the Everolimus plus 30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone (p=0015), or Everolimus alone (p

John M. Kovarik - One of the best experts on this subject based on the ideXlab platform.

  • Sotrastaurin and Everolimus pharmacokinetics after single-dose coadministration.
    International journal of clinical pharmacology and therapeutics, 2010
    Co-Authors: John M. Kovarik, Christiane Rordorf, M. Bartlett, M. C. Antunes, S. Winter, P. Marbach, S. Van Marle
    Abstract:

    INTRODUCTION Sotrastaurin is an immunosuppressant that blocks T-lymphocyte activation via protein kinase C inhibition. The authors determined whether a pharmacokinetic interaction occurs between sotrastaurin and Everolimus, both of which are substrates and inhibitors of CYP3A4. METHODS This was a randomized, three-period, crossover study in 18 healthy subjects. They received single oral doses of (1) 100 mg sotrastaurin, (2) 2 mg Everolimus, and (3) the drug combination. Clinical and pharmacokinetic data were collected to Day 5 after each treatment. RESULTS Coadministration of Everolimus decreased sotrastaurin C(max) from 638 +/- 295 to 539 +/- 211 ng/ml yielding a combination/ monotherapy ratio (90% confidence interval) of 0.87 (0.76 - 1.00). Sotrastaurin total AUC was not altered by Everolimus with values of 3660 +/- 1853 versus 3630 +/- 2006 ng*h/ml and a ratio of 1.00 (0.88 - 1.13). Sotrastaurin increased Everolimus C(max) from 15 +/- 6 to 16 +/- 6 ng/ml yielding a ratio of 1.15 (0.99 - 1.33) and increased Everolimus total AUC from 114 +/- 50 to 137 +/- 56 ng*h/ml yielding a ratio of 1.20 (1.05 - 1.37). The possibility that a higher dose of sotrastaurin than used in this study might further increase Everolimus blood levels cannot be excluded. CONCLUSIONS Coadministration of a single 100 mg dose sotrastaurin with a single 2 mg dose Everolimus did not alter sotrastaurin pharmacokinetics to a clinically relevant extent. Everolimus AUC was increased 20% by sotrastaurin.

  • Differential Pharmacokinetic Interaction of Tacrolimus and Cyclosporine on Everolimus
    Transplantation proceedings, 2006
    Co-Authors: John M. Kovarik, J.j. Curtis, D.e. Hricik, M.d. Pescovitz, V. Scantlebury, A. Vasquez
    Abstract:

    Abstract Objective We characterized the pharmacokinetics of tacrolimus and Everolimus in a combined immunosuppressive regimen. Methods This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with Everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half. Results At study entry tacrolimus trough level (C0) was 7.9 ± 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 ± 56 ng · h/mL. The addition of Everolimus in period 1 did not change tacrolimus exposure: C0 8.4 ± 4.0 ng/mL, AUC 134 ± 70 ng · h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 ± 1.2 ng/mL, Cmax 10.4 ± 5.1 ng/mL, AUC 58 ± 20 ng · h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving Everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, Everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in Everolimus exposure: C0 3.0 ± 1.1 ng/mL, Cmax 8.2 ± 1.3 ng/mL, AUC 49 ± 10 ng · h/mL. Conclusions Tacrolimus appears to have a minimal effect on Everolimus blood levels compared with the influence of cyclosporine. The dose of Everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given Everolimus blood level.

  • Effect of multiple-dose erythromycin on Everolimus pharmacokinetics
    European journal of clinical pharmacology, 2005
    Co-Authors: John M. Kovarik, D. Beyer, M. N. Bizot, Q. Jiang, M. Shenouda, Robert Schmouder
    Abstract:

    We sought to quantify the influence of the CYP3A inhibitor erythromycin on the pharmacokinetics of Everolimus, a CYP3A substrate. This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of Everolimus. In period 2, they received the test treatment of erythromycin 500 mg three times daily for a total of 9 days and a single 2-mg dose of Everolimus coadministered on the fifth day of erythromycin therapy. The test/reference ratio and 90% confidence interval (CI) were derived for Everolimus C max and AUC. During erythromycin coadministration, Everolimus C max increased 2.0-fold (90% CI, 1.8–2.3) from 20±5 ng/ml to 40±10 ng/ml. Everolimus AUC increased 4.4-fold (90% CI, 3.5–5.4) from 116±37 ng h/ml to 524±225 ng h/ml. Everolimus half-life was prolonged by 39% from 32±6 h to 44±6 h. Erythromycin predose concentrations were not changed after single-dose administration of Everolimus. Multiple-dose erythromycin increased single-dose Everolimus blood levels by an average 4.4-fold (range, 2.0–12.6). During erythromycin treatment, a compensatory Everolimus dose reduction should be made guided by Everolimus therapeutic drug monitoring.

  • Blood concentrations of Everolimus are markedly increased by ketoconazole.
    Journal of clinical pharmacology, 2005
    Co-Authors: John M. Kovarik, D. Beyer, M. N. Bizot, Q. Jiang, M. Shenouda, Robert Schmouder
    Abstract:

    The authors sought to quantify the influence of the CYP3A and P-glycoprotein inhibitor ketoconazole on the pharmacokinetics of Everolimus in healthy subjects. This was a 2-period, single-sequence, crossover study in 12 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of Everolimus. In period 2, they received the test treatment of ketoconazole 200 mg twice daily for a total of 8 days and a single dose of Everolimus coadministered on the fourth day of ketoconazole therapy. The test/reference ratio and 90% confidence interval were derived for Everolimus maximum concentration and area under the curve. During ketoconazole coadministration, Everolimus maximum concentration increased 3.9-fold (90% confidence interval, 3.4-4.6) from 15 +/- 4 ng/mL to 59 +/- 13 ng/mL. Everolimus area under the curve increased 15.0-fold (90% confidence interval, 13.6-16.6) from 90 +/- 23 ng*h/mL to 1324 +/- 232 ng*h/mL. Everolimus half-life was prolonged by 1.9-fold from 30 +/- 4 hours to 56 +/- 5 hours. Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in Everolimus-treated patients.

  • Pharmacokinetic interaction between verapamil and Everolimus in healthy subjects
    British journal of clinical pharmacology, 2005
    Co-Authors: John M. Kovarik, D. Beyer, M. N. Bizot, Q. Jiang, M. J. Allison, Robert Schmouder
    Abstract:

    Aims We sought to define the influence of verapamil, an inhibitor of CYP3A and P-glycoprotein, on the pharmacokinetics of Everolimus, a substrate of this enzyme and transporter. Methods This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1 subjects received a single 2 mg oral dose of Everolimus. In period 2 they received verapamil 80 mg three times daily for a total of 6 days and a single 2 mg dose of Everolimus co-administered on the second day of verapamil therapy. Results During verapamil co-administration, Everolimus Cmax increased 2.3-fold (90% CI, 1.9, 2.7) from 21 ± 8 to 47 ± 18 ng ml−1 and AUC increased 3.5-fold (90% CI, 3.1, 3.9) from 115 ± 45 to 392 ± 142 ng ml−1 h. Everolimus half-life was only prolonged to a minor extent (32 ± 6 vs. 37 ± 6 h). Verapamil predose concentrations doubled from 32 ± 16 to 74 ± 42 ng ml−1 after single dose administration of Everolimus. Conclusions Multiple dosing with verapamil increased blood concentrations of Everolimus after a single dose by an average 3.5-fold. During verapamil treatment, dose reduction for Everolimus should be made guided by blood monitoring and for verapamil by blood pressure monitoring.

Helena J. Mauceri - One of the best experts on this subject based on the ideXlab platform.

  • Everolimus exhibits efficacy as a radiosensitizer in a model of non small cell lung cancer
    Oncology Reports, 2012
    Co-Authors: Helena J. Mauceri, Harold G. Sutton, Thomas E. Darga, Masha Kocherginsky, Joel Kochanski, Ralph R. Weichselbaum, Everett E. Vokes
    Abstract:

    Signaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition can restore sensitivity to DNA damaging agents such as cisplatin. The rapamycin derivative Everolimus exhibits antitumor activity and is approved for patients with renal cell cancer. Clinically, Everolimus has also been evaluated in patients with advanced non-small cell lung cancer (NSCLC) that were refractory to chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors. We tested the effects of combined treatment with Everolimus (RAD001) and fractionated radiation using a xenograft model of human NSCLC (A549 cells). In growth studies, mean tumor volume was reduced in the Everolimus plus 30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone (p=0015), or Everolimus alone (p<0.001, ANOVA). Everolimus (20 nM) significantly reduced protein levels of the mTOR downstream effector p70-S6K compared with radiation and vehicle (p=0.05, ANOVA) and significantly suppressed phospho-p70-S6K levels compared with all other treatments (p<0.001, ANOVA). We also evaluated Everolimus and radiation effects on gene expression in A549 cells. Everolimus ± 5 Gy suppressed endothelin 1 and lactate dehydrogenase expression and increased VEGFA, p21, hypoxia-inducible factor-1α and SLC2A1 (facilitated glucose transporter 1). mTOR mRNA levels were unaffected while TNF-α levels were increased with Everolimus + 5 Gy compared to either treatment alone. These findings suggest that Everolimus increases the antitumor activity of radiation. Clinical trials combining Everolimus with fractionated radiation in patients with NSCLC are warranted.

  • Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer
    Oncology Reports, 2012
    Co-Authors: Helena J. Mauceri, Harold G. Sutton, Thomas E. Darga, Masha Kocherginsky, Joel Kochanski, Ralph R. Weichselbaum, Everett E. Vokes
    Abstract:

    : Signaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition can restore sensitivity to DNA damaging agents such as cisplatin. The rapamycin derivative Everolimus exhibits antitumor activity and is approved for patients with renal cell cancer. Clinically, Everolimus has also been evaluated in patients with advanced non-small cell lung cancer (NSCLC) that were refractory to chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors. We tested the effects of combined treatment with Everolimus (RAD001) and fractionated radiation using a xenograft model of human NSCLC (A549 cells). In growth studies, mean tumor volume was reduced in the Everolimus plus 30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone (p=0015), or Everolimus alone (p

Randall C Starling - One of the best experts on this subject based on the ideXlab platform.

  • Everolimus versus mycophenolate mofetil in heart transplantation a randomized multicenter trial
    American Journal of Transplantation, 2013
    Co-Authors: Howard J Eisen, Randall C Starling, J Kobashigawa, Daniel F Pauly, Abdallah G Kfoury, Heather J Ross, Shoeishen Wang, Bernard Cantin, A Van Bakel, G A Ewald
    Abstract:

    In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to Everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard-dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: -7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with Everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (Everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with Everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with Everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

  • therapeutic drug monitoring for Everolimus in heart transplant recipients based on exposure effect modeling
    American Journal of Transplantation, 2004
    Co-Authors: Randall C Starling, John M. Kovarik, Joshua M Hare, Paul J Hauptman, Kenneth R Mccurry, Hartmut W Mayer, Heinz Schmidli
    Abstract:

    Everolimus, a proliferation signal inhibitor, is an immunosuppressant that targets the primary causes of progressive allograft dysfunction, thus improving the long-term outcome after heart transplantation. The present study investigated whether therapeutic drug monitoring (TDM) of Everolimus would benefit heart transplant patients. Data from a twelve-month phase III trial comparing Everolimus (1.5 or 3 mg daily) with azathioprine were used to evaluate Everolimus pharmacokinetics, exposure-efficacy/safety and TDM prognostic simulations. Everolimus trough levels were stable in the first year post-transplant and averaged 5.2 ± 3.8 and 9.4 ± 6.3 ng/mL in patients treated with 1.5 and 3 mg/day, respectively. Cyclosporine trough levels were similar in all treatment groups. Biopsy-proven acute rejection (BPAR) was reduced with Everolimus trough levels ≥3 ng/mL. Intravascular ultrasound (IVUS) analysis showed evidence of reduced vasculopathy at 12 months with increasing Everolimus exposure. Unlike cyclosporine, increasing Everolimus exposure was not related to a higher rate of renal dysfunction. The TDM simulation, which was based on two Everolimus dose adjustments and an initial starting dose of 1.5 mg/day, showed that the simulated BPAR rate (with TDM) was 21% versus 26% in the group with fixed dosing. Therefore, TDM in heart transplantation could optimize immunosuppressive efficacy and reduce treatment-related toxicity.

  • Everolimus for the prevention of allograft rejection and vasculopathy in cardiac transplant recipients
    The New England Journal of Medicine, 2003
    Co-Authors: Howard J Eisen, Randall C Starling, J Kobashigawa, Murat E Tuzcu, R Dorent, Donna Mancini, Hannah Valantinevon A Kaeppler, Keld Sorensen, M Hummel, Joan M Lind
    Abstract:

    Background Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. We conducted a randomized, double-blind, clinical trial comparing Everolimus with azathioprine in recipients of a first heart transplant. Methods A total of 634 patients were randomly assigned to receive 1.5 mg of Everolimus per day (209 patients), 3.0 mg of Everolimus per day (211 patients), or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A, or rejection with hemodynamic compromise. Results At six months, the percentage of patients who had reached the primary efficacy end point was significantly smaller in the group given 3.0 mg of Everolimus (27.0 percent, P<0.001) and the group given 1.5 mg of Everolimus (36.4 percent, P=0.03) tha...

Julio Pascual - One of the best experts on this subject based on the ideXlab platform.

  • Everolimus with reduced calcineurin inhibitor exposure in renal transplantation
    Journal of The American Society of Nephrology, 2018
    Co-Authors: Julio Pascual, Stefan P Berger, Oliver Witzke, H Tedesco, Shamkant Mulgaonkar, Y Qazi, Steven J Chadban, Federico Oppenheimer, Claudia Sommerer, Rainer Oberbauer
    Abstract:

    Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, Everolimus with reduced-exposure CNI (Everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (Everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with Everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with Everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the Everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with Everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, Everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

  • The use of Everolimus in renal-transplant patients
    International journal of nephrology and renovascular disease, 2009
    Co-Authors: Julio Pascual
    Abstract:

    Despite advances in immunosuppressive therapy, long-term renal-transplantation outcomes have not significantly improved over the last decade. The nephrotoxicity of calcineurin inhibitors (CNIs) is an important cause of chronic allograft nephropathy (CAN), the major driver of long-term graft loss. Everolimus is a proliferation signal inhibitor with a mechanism of action that is distinct from CNIs. The efficacy and tolerability of Everolimus in renal-transplant recipients have been established in a wide range of clinical trials. Importantly, synergism between Everolimus and the CNI cyclosporine (CsA) permits CsA dose reduction, enabling nephrotoxicity to be minimized without compromising efficacy. Currently, Everolimus is being investigated in regimens where reduced exposure CNIs are used from the initial post-transplant period to improve renal function and prevent CAN. By inhibiting the proliferation of smooth muscle cells, Everolimus may itself delay the progression or development of CAN. Although Everolimus is associated with specific side effects, these can generally be managed. By targeting the main causes of short- and long-term graft loss, Everolimus has a key role to play in renal transplantation, which is being explored further in a number of ongoing Phase III-IV trials.

  • Clinical experience with Everolimus (Certican): optimizing dose and tolerability.
    Transplantation, 2005
    Co-Authors: Julio Pascual, Roberto Marcén, Joaquín Ortuño
    Abstract:

    Everolimus (Certican), a novel proliferation signal inhibitor, allows calcineurin inhibitor dose reduction in transplant patients, minimizing risk of nephrotoxicity without loss of immunosuppressive efficacy. As a result of its mode of action, this class of agent (i.e., Everolimus and sirolimus) is associated with certain adverse events (e.g., lymphocele, arthralgia, edema and hyperlipidemia). Three case studies from within an Everolimus Phase III trial (A2306) are presented with the aim of illustrating how treatment-related adverse events can be managed. The combination of Everolimus with reduced-exposure cyclosporine was efficacious in these patients. One experienced mild acute rejection that was managed with steroid boluses. All have acceptable graft function during follow-up to date. Moderate lymphocele either resolved spontaneously or was easily managed by povidine-iodine instillations. One patient developed serious early lymphocele that, unusually, required surgical intervention. Everolimus dose reduction or withdrawal was not necessary to effectively manage lymphocele of any severity. A case of bilateral multiple arthralgia was effectively managed with Everolimus dose reduction, but still maintained Everolimus trough blood levels at approximately 3 ng/ml. Eyelid and ankle edemas were also easily managed with low dose furosemide, preferably coupled with cyclosporine and Everolimus dose reduction. Hyperlipidemia responded to statin therapy. Everolimus-related adverse events can be effectively managed either with other treatments or, where necessary, by Everolimus dose reduction, without loss of efficacy. Discontinuing Everolimus therapy is generally not necessary.

  • Clinical experience with Everolimus (Certican): optimizing dose and tolerability.
    Transplantation, 2005
    Co-Authors: Julio Pascual, Roberto Marcén, Joaquín Ortuño
    Abstract:

    Background. Everolimus (Certican), a novel proliferation signal inhibitor, allows calcineurin inhibitor dose reduction in transplant patients, minimizing risk ofnephrotoxicity without loss of immunosuppressive efficacy. As a result of its mode of action, this class of agent (i.e., Everolimus and sirolimus) is associated with certain adverse events (e.g., lymphocele, arthralgia, edema and hyperlipidemia). Methods. Three case studies from within an Everolimus Phase III trial (A2306) are presented with the aim of illustrating how treatment-related adverse events can be managed. Results. The combination of Everolimus with reduced-exposure cyclosporine was efficacious in these patients. One experienced mild acute rejection that was managed with steroid boluses. All have acceptable graft function during follow-up to date. Moderate lymphocele either resolved spontaneously or was easily managed by povidine-iodine instillations. One patient developed serious early lymphocele that, unusually, required surgical intervention. Everolimus dose reduction or withdrawal was not necessary to effectively manage lymphocele ofany severity. A case of bilateral multiple arthralgia was effectively managed with Everolimus dose reduction, but still maintained Everolimus trough blood levels at approximately 3 ng/ml. Eyelid and ankle edemas were also easily managed with low dose furosemide, preferably coupled with cyclosporine and Everolimus dose reduction. Hyperlipidemia responded to statin therapy. Conclusions. Everolimus-related adverse events can be effectively managed either with other treatments or, where necessary, by Everolimus dose reduction, without loss of efficacy. Discontinuing Everolimus therapy is generally not necessary.