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Everolimus transplantation

Ida Robertsen, Jean Debord, Anders Åsberg, Pierre Marquet, Jean-Baptiste Woillard
BACKGROUND AND OBJECTIVE: Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients. METHODS: Full whole blood and PBMC concentration-time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart...
March 20, 2018: Clinical Pharmacokinetics
Hideaki Kagaya, Takenori Niioka, Mitsuru Saito, Takamitsu Inoue, Kazuyuki Numakura, Ryohei Yamamoto, Yumiko Akamine, Tomonori Habuchi, Shigeru Satoh, Masatomo Miura
While tacrolimus and everolimus have common metabolic pathways through CYP3A4/5, tacrolimus is metabolized solely by CYP3A4 in recipients with the CYP3A5*3 / *3 . The purpose of this study was to evaluate how the area under the blood concentration-time curves (AUC) of tacrolimus could be predicted based on CYP3A5 genotype and the AUC of everolimus in renal transplant patients taking both drugs. The dose-adjusted AUC (AUC/D) of tacrolimus and everolimus were calculated at one month and one year after transplantation...
March 16, 2018: International Journal of Molecular Sciences
Shin Hwang, Chul-Soo Ahn, Ki-Hun Kim, Deok-Bog Moon, Tae-Yong Ha, Gi-Won Song, Dong-Hwan Jung, Gil-Chun Park, Sung-Gyu Lee
Backgrounds/Aims: Long-term immunosuppression regimens after liver transplantation (LT) are rarely reported in detail. We aimed to provide information on actual long-term immunosuppression regimens through this cross-sectional study. Methods: Our institutional LT database was searched for adult patients who underwent primary LT operation from 2000 to 2016. We identified 3620 live recipients with actual information on immunosuppressive agent use for 1-17 years. Results: The study cohort was divided into 7 groups according to posttransplantation period...
February 2018: Annals of Hepato-Biliary-Pancreatic Surgery
Neha Mehta-Shah, Nancy L Bartlett
Addition of brentuximab vedotin, a CD30 targeted antibody-drug conjugate, and the PD-1 inhibitors, nivolumab and pembrolizumab, to the armamentarium for transplant-ineligible relapsed/refractory classical Hodgkin lymphoma has resulted in improved outcomes, including the potential for cure in a small minority of patients. For patients who have failed prior transplant or are unsuitable for dose-intense approaches based on age or comorbidities, an individualized approach with sequential use of single agents such as brentuximab vedotin, PD-1 inhibitors, everolimus, lenalidomide, or conventional agents such as gemcitabine or vinorelbine, may result in prolonged survivals with minimal or modest effect on quality of life...
March 2, 2018: Blood
Yi-Ping Jin, Nicole M Valenzuela, Xiaohai Zhang, Enrique Rozengurt, Elaine F Reed
Transplant recipients developing donor-specific HLA class II (HLA-II) Abs are at higher risk for Ab-mediated rejection (AMR) and transplant vasculopathy. To understand how HLA-II Abs cause AMR and transplant vasculopathy, we determined the signaling events triggered in vascular endothelial cells (EC) following Ab ligation of HLA-II molecules. HLA-II expression in EC was induced by adenoviral vector expression of CIITA or by pretreatment with TNF-α/IFN-γ. Ab ligation of class II stimulated EC proliferation and migration...
February 23, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
T M Manzia, R Angelico, L Toti, C Grimaldi, D Sforza, I Vella, L Tariciotti, I Lenci, G Breshanaj, L Baiocchi, G Tisone
AIM: We designed a retrospective case-control study to determine the efficacy and feasibility of everolimus (EVR) combined with low-dose tacrolimus (Tac) ab initio versus standard-dose Tac after liver transplantation (LT). METHODS: Seventy-one adult LT patients, receiving EVR and low-dose Tac without corticosteroids or induction therapy from postoperative day 1 (EVR group) were compared with a well-matched control group of 61 recipients treated with standard-dose Tac in association with antimetabolite...
January 2018: Transplantation Proceedings
Narin Ozturk, Dilek Ozturk, Zeliha Pala-Kara, Engin Kaptan, Serap Sancar-Bas, Nurten Ozsoy, Suzan Cinar, Gunnur Deniz, Xiao-Mei Li, Sylvie Giacchetti, Francis Lévi, Alper Okyar
The circadian timing system controls many biological functions in mammals including xenobiotic metabolism, detoxification, cell proliferation, apoptosis and immune functions. Everolimus is a mammalian target of rapamycin inhibitor, whose immunosuppressant properties are both desired in transplant patients and unwanted in cancer patients, where it is indicated for its antiproliferative efficacy. Here we sought whether everolimus circadian timing would predictably modify its immunosuppressive effects so as to optimize this drug through timing...
February 5, 2018: Chronobiology International
R Bouamar, N Shuker, J A J Osinga, M C Clahsen-van Groningen, J Damman, C C Baan, J van de Wetering, A T Rowshani, J Kal-van Gestel, W Weimar, T van Gelder, D A Hesselink
BACKGROUND: While conversion from cyclosporine to everolimus is well documented, conversion from tacrolimus has been poorly studied. In this randomised, controlled trial the safety and tolerability of switching from tacrolimus to everolimus with glucocorticoid withdrawal after living-donor kidney transplantation was studied. METHODS: A total of 194 patients were planned to be randomised 1:1 to either continue tacrolimus or to convert to everolimus at month 3 after transplantation...
January 2018: Netherlands Journal of Medicine
Maggie K M Ma, Susan Yung, Tak Mao Chan
Mammalian or mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that plays essential roles in cell growth, proliferation, metabolism, and survival. Increased activation of the mTOR pathway is observed in patients and animal models of renal transplant rejection, autosomal dominant polycystic kidney disease, renal cell carcinoma, diabetic nephropathy, lupus nephritis, and angiomyolipoma. Agents that inhibit mTOR, such as sirolimus and everolimus, are incorporated in immunosuppressive regimens to prevent renal allograft rejection and are often used to facilitate calcineurin inhibitor minimization or to reduce the incidence of tumor recurrence...
February 2018: Transplantation
Arnaud Devresse, Marianne Leruez-Ville, Anne Scemla, Véronique Avettand-Fenoel, Lise Morin, Xavier Lebreton, Claire Tinel, Lucile Amrouche, Lionel Lamhaut, Marc Olivier Timsit, Julien Zuber, Christophe Legendre, Dany Anglicheau
BACKGROUND: donor (D)+/recipient (R)- serostatus is closely associated with a higher risk of cytomegalovirus (CMV) infection and disease. Antiviral prophylaxis is conventionally used in such patients, but late-onset CMV infection/disease still occurs after the discontinuation of prophylaxis. METHODS: we retrospectively analyzed the data of 215 low immunological risk patients who received kidney transplantation in our center between 2011 and 2016. RESULTS: ninety-seven patients received a combination of everolimus (EVL)/reduced doses of calcineurin inhibitors (CNI) (EVL group) de novo, and 118 received a combination of mycophenolic acid (MPA)/standard doses of CNI (MPA group) de novo...
January 23, 2018: Transplant Infectious Disease: An Official Journal of the Transplantation Society
Manon Launay, Antoine Roux, Laurence Beaumont, Benoit Douvry, Lucien Lecuyer, Emmanuel Douez, Clément Picard, Dominique Grenet, Vincent Jullien, Véronique Boussaud, Romain Guillemain, Eliane M Billaud
Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations ( C 0 ) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure...
March 2018: Antimicrobial Agents and Chemotherapy
Long-Bin Jeng, Sung Gyu Lee, Arvinder Singh Soin, Wei-Chen Lee, Kyung-Suk Suh, Dong Jin Joo, Shinji Uemoto, Jaewon Joh, Tomoharu Yoshizumi, Horng-Ren Yang, Gi-Won Song, Patricia Lopez, Jossy Kochuparampil, Carole Sips, Shuhei Kaneko, Gary Levy
In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized at 30±5 days post-transplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non-inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months post-transplant: difference -0.7% [90%CI -5.2%, 3.7%]; p<0.001 for non-inferiority. tBPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated GFR from randomization to month 12, achieved non-inferiority (p<0...
December 13, 2017: American Journal of Transplantation
Alain G Verstraete, Raül Rigo-Bonnin, Pierre Wallemacq, Michael Vogeser, Andre Schuetzenmeister, Christian Schmiedel, Maria Shipkova
BACKGROUND: The precise monitoring of everolimus, an immunosuppressant drug, is vital for transplant recipients due to its narrow therapeutic range. This study evaluated the analytical performance of a new electrochemiluminescence immunoassay (ECLIA) for everolimus concentrations in whole blood. METHODS: Accuracy, imprecision, and sensitivity studies for the Roche Elecsys everolimus ECLIA were performed at 5 European laboratories. The ECLIA was compared with liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, as well as the Quantitative Microsphere System everolimus assay...
February 2018: Therapeutic Drug Monitoring
Y Kumai, O Seguchi, T Sato, K Wada, M Shiozawa, C Yokota, K Kuroda, S Nakajima, T Sato, M Yanase, Y Matsumoto, S Fukushima, T Fujita, J Kobayashi, N Fukushima
BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a transient cerebrovascular disorder putatively caused by some immunosuppressive agents. CASE REPORT: We recently encountered a 47-year-old female patient diagnosed with dilated cardiomyopathy who developed RCVS after heart transplantation. A triple-drug regimen consisting of tacrolimus, mycophenolate mofetil, and a corticosteroid was started after surgery. On postoperative day (POD) 11, the patient developed a severe headache, although computed tomography of the head demonstrated no signs of hemorrhage or infarction...
December 2017: Transplantation Proceedings
Khaldoun Ghazal, Fabien Stenard, Géraldine Dahlqvist, Clément Barjon, Lynda Aoudjehane, Olivier Scatton, Filomena Conti
BACKGROUND: The mammalian targets of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVR]) are used after transplantation for their immunosuppressive activity. Regulatory T-cells (Tregs) play a crucial role in immune tolerance. mTOR inhibitors appear to preserve Tregs, unlike Tacrolimus (Tac). AIM: The aim of this study was to evaluate the number and function of Tregs in liver transplant recipients before and after conversion from Tac to mTOR inhibitors...
November 22, 2017: Clinics and Research in Hepatology and Gastroenterology
Narendra Singh Choudhary, Neeraj Saraf, Sanjiv Saigal, Dheeraj Gautam, Amit Rastogi, Sanjay Goja, Prashant Bhangui, Thiagrajan Srinivasan, Sanjay Kumar Yadav, Arvinder Soin
BACKGROUND AND AIMS: Chronic rejection (CR) is an uncommon but important cause of graft dysfunction, leading to graft loss and often requires re-transplantation. This study evaluates the incidence and outcome of patients with CR at a large living donor liver transplant (LDLT) centre. METHODS: Data of patients with CR was retrospectively analyzed in 1232 adult (age >18 years) LDLT on Tacrolimus (mainly) based immunosuppression. Sirolimus/Everolimus (mTOR inhibitors) were added to baseline immunosuppression as rescue therapy in patients with CR...
November 21, 2017: Clinical Transplantation
Daniel Reichart, Hermann Reichenspurner, Markus Johannes Barten
Renal dysfunction caused by calcineurin inhibitor (CNI) nephrotoxicity occurs often and contributes significantly to late mortality after heart transplantation (HTx). Over the last decades, this has prompted many clinical studies in an effort to develop kidney-protecting immunosuppressive strategies including delayed CNI start, minimization, withdrawal, or even de novo CNI avoidance. In the past, these strategies often failed due to the lack of efficacy. Since 2009, novel CNI-reducing strategies have been under investigation...
January 2018: Clinical Transplantation
Lotte M Knapen, Yvo de Beer, Roger J M Brüggemann, Leo M Stolk, Frank de Vries, Vivianne C G Tjan-Heijnen, Nielka P van Erp, Sander Croes
While the therapeutic drug monitoring (TDM) of everolimus has been routinely performed for over 10 years in solid organ transplantation medicine, in order to optimize the balance between effectiveness and toxicity, it is yet uncommon in the treatment of malignancies. The aim of this study was to develop and validate a bioanalytical method to quantify everolimus in dried blood spots (DBS) to facilitate TDM for the oncology outpatient setting. The hematocrit effect of everolimus was investigated. An 7.5mm disk from the central part of the DBS was punched, followed by the extraction of everolimus from the DBS by methanol/acetonitrile (80/20%) spiked with deuterium-labelled everolimus as internal standard...
October 29, 2017: Journal of Pharmaceutical and Biomedical Analysis
Alexandra Frey, Katja Piras-Straub, Andreas Walker, Jörg Timm, Guido Gerken, Kerstin Herzer
BACKGROUND: Direct-acting antivirals (DAA) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified. METHODS: Subgenomic HCV replicons for genotype (GT) 1b, 2b, 3a and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNI) cyclosporine or tacrolimus, either alone or in combination with selected DAAs...
November 7, 2017: Transplant Infectious Disease: An Official Journal of the Transplantation Society
Yu-Hua Chao, Yin-Chen Chang, Han-Ping Wu, Ching-Tien Peng, Te-Fu Weng, Kang-Hsi Wu
Acute graft-versus-host disease (aGVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Due to the poor prognosis for patients not responding to first-line steroids treatment, improvements in aGVHD therapy are needed. Everolimus is a promising candidate that combines immunosuppressive properties with anti-neoplastic effects. Here, we retrospectively reviewed the efficacy of everolimus with steroids as primary treatment in 13 patients with grade II to grade IV aGVHD after HSCT...
November 2017: Medicine (Baltimore)
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