{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T04:38:07Z","timestamp":1784003887982,"version":"3.55.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:title>Abstract:<\/jats:title>\n          <jats:p>Pharmacodynamic (PD) monitoring may complement routine pharmacokinetic monitoring of mTOR inhibitors (mTORis) in an attempt to better guide individualized sirolimus (SRL) or everolimus (EVR) treatment after organ transplantation. This review focuses on current knowledge about PD biomarkers for personalized mTORi therapies. Different strategies have already been used in the evaluation of the pharmacodynamics of SRL and EVR as a proxy for their effects on the immune response after transplantation. These include measuring p70S6K (70 kDa ribosomal protein S6 kinase) activity, p70S6K phosphorylation (P-p70S6K), or P-S6 protein expression. Compared with Western blot and ELISA, phosphoflow cytometry can detect phosphorylated proteins and differentiate activation-induced changes of signaling molecules inside the cell from unstimulated populations of identical cells in the same sample. Alternatively, in patients receiving a combined therapy, the other PD approach is to consider biomarkers such as NFAT residual expression for calcineurin inhibitors or to evaluate nonspecific effects of the drugs such as lymphocyte proliferation, interleukin synthesis, specific peripheral blood T regulatory subsets, or lymphocyte surface antigens, which have the advantage to reflect the overall immunosuppressive status achieved. Although limited, the available data on mTOR pathway biomarkers seem promising. Before clinical implementation, the analytical methodologies must be standardized and cross-validated, and the selected biomarkers will have to demonstrate their clinical utility for SRL or EVR dose individualization in multicenter clinical trials.<\/jats:p>","DOI":"10.1097\/ftd.0000000000000616","type":"journal-article","created":{"date-parts":[[2019,3,3]],"date-time":"2019-03-03T05:43:55Z","timestamp":1551591835000},"page":"160-167","source":"Crossref","is-referenced-by-count":14,"title":["Pharmacodynamic Monitoring of mTOR Inhibitors"],"prefix":"10.1097","volume":"41","author":[{"given":"Olga","family":"Mill\u00e1n","sequence":"first","affiliation":[{"name":"Pharmacology and Toxicology Laboratory, Biomedical Diagnostic Center (CDB), CIBERehd, IDIBAPS, Hospital Cl\u00ednic of Barcelona, University of Barcelona, Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eberhard","family":"Wieland","sequence":"additional","affiliation":[{"name":"Zentralinstitut f\u00fcr Klinische Chemie und Laboratoriumsmedizin, Klinikum Stuttgart, Stuttgart, Germany; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Marquet","sequence":"additional","affiliation":[{"name":"U1248 Pharmacology and Transplantation INSERM, CHU Limoges, University of Limoges, Limoges, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Brunet","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Laboratory, Biomedical Diagnostic Center (CDB), CIBERehd, IDIBAPS, Hospital Cl\u00ednic of Barcelona, University of Barcelona, Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20230814","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","article-title":"TOR signaling in growth and metabolism","volume":"124","author":"Wullschleger","year":"2006","journal-title":"Cell."},{"key":"R2-20230814","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1007\/s00280-014-2435-7","article-title":"Impact of everolimus blood concentration on its anti-cancer activity in patients with metastatic renal cell carcinoma","volume":"73","author":"Thiery-Vuillemin","year":"2014","journal-title":"Cancer Chemother Pharmacol."},{"key":"R3-20230814","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJMoa1109653","article-title":"Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer","volume":"366","author":"Baselga","year":"2012","journal-title":"N Engl J Med."},{"key":"R4-20230814","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0140-6736(12)61767-X","article-title":"Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial","volume":"381","author":"Bissler","year":"2013","journal-title":"Lancet."},{"key":"R5-20230814","doi-asserted-by":"crossref","first-page":"5549","DOI":"10.1158\/0008-5472.CAN-05-2825","article-title":"Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus","volume":"66","author":"Del Bufalo","year":"2006","journal-title":"Cancer Res."},{"key":"R6-20230814","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ccr.2006.07.003","article-title":"Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin","volume":"10","author":"Phung","year":"2006","journal-title":"Cancer Cell."},{"key":"R7-20230814","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1097\/FTD.0000000000000260","article-title":"Therapeutic drug monitoring of everolimus: a consensus report","volume":"38","author":"Shipkova","year":"2016","journal-title":"Ther Drug Monit."},{"key":"R8-20230814","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.clinbiochem.2016.01.005","article-title":"Editorial: immune monitoring in solid organ transplantation","volume":"49","author":"Shipkova","year":"2016","journal-title":"Clin Biochem."},{"issue":"suppl 1","key":"R9-20230814","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1097\/FTD.0000000000000288","article-title":"Target enzyme activity and phosphorylation of pathway molecules as specific biomarkers in transplantation","volume":"38","author":"Budde","year":"2016","journal-title":"Ther Drug Monit."},{"key":"R10-20230814","first-page":"3058","article-title":"P70 S6 kinase assay: a pharmacodynamic monitoring strategy for rapamycin; assay development","volume":"28","author":"Gallant","year":"1996","journal-title":"Transpl Proc."},{"key":"R11-20230814","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/0076-6879(91)00146-N","article-title":"Purification and properties of mitogen-activated S6 kinase from rat liver and 3T3 cells","volume":"200","author":"Lane","year":"1991","journal-title":"Meth Enzymol."},{"key":"R12-20230814","first-page":"2887","article-title":"Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients","volume":"9","author":"Peralba","year":"2003","journal-title":"Clin Cancer Res."},{"key":"R13-20230814","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1053\/j.ajkd.2007.05.002","article-title":"Monitoring biological action of rapamycin in renal transplantation","volume":"50","author":"Leogrande","year":"2007","journal-title":"Am J Kidney Dis."},{"key":"R14-20230814","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1111\/j.1523-1755.2005.00731.x","article-title":"Biochemical monitoring of mTOR inhibitor-based immunosuppression following kidney transplantation: a novel approach for tailored immunosuppressive therapy","volume":"68","author":"Hartmann","year":"2005","journal-title":"Kidney Int."},{"key":"R15-20230814","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ab.2010.04.022","article-title":"A spectrophotometric assay for routine measurement of mammalian target of rapamycin activity in cell lysates","volume":"403","author":"Dekter","year":"2010","journal-title":"Anal Biochem."},{"key":"R16-20230814","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1097\/FTD.0b013e3182804c9b","article-title":"Development of a sensitive phospho-p70 S6 kinase ELISA to quantify mTOR proliferation signal inhibition","volume":"35","author":"Hartmann","year":"2013","journal-title":"Ther Drug Monit."},{"key":"R17-20230814","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/cyto.b.21005","article-title":"Assay validation of phosphorylated S6 ribosomal protein for a pharmacodynamic monitoring of mTOR-inhibitors in peripheral human blood","volume":"82","author":"Dieterlen","year":"2012","journal-title":"Cytometry B Clin Cytom."},{"key":"R18-20230814","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0092-8674(00)00114-8","article-title":"Cell signaling by receptor tyrosine kinases","volume":"103","author":"Schlessinger","year":"2000","journal-title":"Cell."},{"key":"R19-20230814","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1089\/adt.2006.044","article-title":"Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts","volume":"5","author":"Gowan","year":"2007","journal-title":"Assay Drug Dev Technol."},{"key":"R20-20230814","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1177\/1087057114545650","article-title":"Detection of PI3K Inhibition in human neuroblastoma using multiplex Luminex bead immunoassay: a targeted approach for pathway analysis","volume":"19","author":"Lang","year":"2014","journal-title":"J Biomol Screen."},{"key":"R21-20230814","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.clinbiochem.2016.06.012","article-title":"Performance of a phosphoflow assay to determine phosphorylation of S6 ribosomal protein as a pharmacodynamic read out for mTOR inhibition","volume":"49","author":"Abdel-Kahaar","year":"2016","journal-title":"Clin Biochem."},{"key":"R22-20230814","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1158\/0008-5472.CAN-3554-2","article-title":"Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells","volume":"64","author":"Boulay","year":"2004","journal-title":"Cancer Res."},{"key":"R23-20230814","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1200\/JCO.2007.14.0988","article-title":"Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors","volume":"26","author":"O'Donnell","year":"2008","journal-title":"J Clin Oncol."},{"key":"R24-20230814","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1097\/FTD.0000000000000287","article-title":"Barcelona consensus on biomarker-based immunosuppressive drugs management in solid organ transplantation","volume":"38","author":"Brunet","year":"2016","journal-title":"Ther Drug Monit."},{"key":"R25-20230814","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/j.1600-6143.2005.00758.x","article-title":"Everolimus and basiliximab permit suppression by human CD4+CD25+ cells in vitro","volume":"5","author":"Game","year":"2005","journal-title":"Am J Transpl."},{"key":"R26-20230814","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/S0167-5699(00)01593-0","article-title":"Bioenergetics of immune functions: fundamental and therapeutic aspects","volume":"21","author":"Buttgereit","year":"2000","journal-title":"Immunol Today."},{"key":"R27-20230814","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1016\/j.cca.2012.01.033","article-title":"Confronting the challenge: individualized immune monitoring after organ transplantation using the cellular immune function assay","volume":"413","author":"Israeli","year":"2012","journal-title":"Clin Chim Acta."},{"key":"R28-20230814","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1016\/j.transproceed.2010.07.045","article-title":"Number of peripheral blood regulatory T cells and lymphocyte activation at 3 months after conversion to mTOR inhibitor therapy","volume":"42","author":"San Segundo","year":"2010","journal-title":"Transpl Proc."},{"key":"R29-20230814","doi-asserted-by":"crossref","first-page":"e5994","DOI":"10.1371\/journal.pone.0005994","article-title":"Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin","volume":"4","author":"Strauss","year":"2009","journal-title":"PLoS One."},{"key":"R30-20230814","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1097\/01.TP.0000116565.86752.6B","article-title":"Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome","volume":"77","author":"Meloni","year":"2004","journal-title":"Transplantation."},{"key":"R31-20230814","doi-asserted-by":"crossref","first-page":"e0156535","DOI":"10.1371\/journal.pone.0156535","article-title":"Immunoregulatory effects of everolimus on in vitro alloimmune responses","volume":"11","author":"Levitsky","year":"2016","journal-title":"PLoS One."},{"key":"R32-20230814","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.trim.2014.05.002","article-title":"Focus on mTOR inhibitors and tacrolimus in renal transplantation: pharmacokinetics, exposure-response relationships, and clinical outcomes","volume":"31","author":"Shihab","year":"2014","journal-title":"Transpl Immunol."},{"key":"R33-20230814","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1365-2184.2007.00413.x","article-title":"Pharmacodynamics of T-cell function for monitoring immunosuppression","volume":"40","author":"Barten","year":"2007","journal-title":"Cell Prolif."},{"key":"R34-20230814","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1111\/j.1432-2277.2012.01537.x","article-title":"Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation","volume":"25","author":"Matz","year":"2012","journal-title":"Transpl Int."},{"key":"R35-20230814","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.intimp.2013.02.025","article-title":"Combined standard and novel immunosuppressive substances affect B-lymphocyte function","volume":"15","author":"Matz","year":"2013","journal-title":"Int Immunopharmacol."},{"key":"R36-20230814","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/ki.2010.269","article-title":"Maintenance immunosuppressive therapy with everolimus preserves humoral immune responses","volume":"78","author":"Struijk","year":"2010","journal-title":"Kidney Int."},{"key":"R37-20230814","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1111\/j.1600-6143.2006.01355.x","article-title":"Phosphorylated S6 ribosomal protein: a novel biomarker of antibody-mediated rejection in heart allografts","volume":"6","author":"Lepin","year":"2006","journal-title":"Am J Transpl."},{"key":"R38-20230814","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/TP.0000000000000273","article-title":"Pharmacodynamic monitoring of mammalian target of rapamycin inhibition by phospho-flow cytometric determination of p70s6 kinase activity","volume":"99","author":"Hoerning","year":"2015","journal-title":"Transplantation."},{"key":"R39-20230814","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cyto.2008.02.015","article-title":"Pharmacodynamic effects of everolimus on anti-CD3 antibody-stimulated T-lymphocyte proliferation and interleukin-10 synthesis in stable kidney-transplant patients","volume":"42","author":"B\u00f6hler","year":"2008","journal-title":"Cytokine."},{"key":"R40-20230814","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/ctr.12331","article-title":"Utility of immune monitoring in heart transplant recipients on everolimus-based immune suppression","volume":"28","author":"Ben Gal","year":"2014","journal-title":"Clin Transpl."},{"key":"R41-20230814","doi-asserted-by":"crossref","first-page":"481","DOI":"10.4049\/jimmunol.1701477","article-title":"mTOR Complex 1 signaling regulates the generation and function of central and effector FOXP3+ regulatory T cells","volume":"201","author":"Sun","year":"2018","journal-title":"J Immunol."},{"key":"R42-20230814","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.2217\/fon.14.31","article-title":"Safety profile and treatment response of everolimus in different solid tumors: an observational study","volume":"10","author":"Verzoni","year":"2014","journal-title":"Future Oncol."},{"key":"R43-20230814","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/bjc.2012.47","article-title":"Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum","volume":"106","author":"Yoon","year":"2012","journal-title":"Br J Cancer."},{"key":"R44-20230814","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1007\/s10637-014-0089-2","article-title":"Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors","volume":"32","author":"Rangwala","year":"2014","journal-title":"Invest New Drugs."},{"key":"R45-20230814","doi-asserted-by":"crossref","first-page":"e89449","DOI":"10.1371\/journal.pone.0089449","article-title":"The relevance of testing the efficacy of anti-angiogenesis treatments on cells derived from primary tumors: a new method for the personalized treatment of renal cell carcinoma","volume":"9","author":"Gr\u00e9pin","year":"2014","journal-title":"PLoS One."},{"key":"R46-20230814","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.it.2007.08.009","article-title":"Do most lymphocytes in humans really reside in the gut?","volume":"28","author":"Ganusov","year":"2007","journal-title":"Trends Immunol."}],"container-title":["Therapeutic Drug Monitoring"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/00007691-201904000-00007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T22:34:49Z","timestamp":1692052489000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/00007691-201904000-00007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.1097\/ftd.0000000000000616","relation":{},"ISSN":["0163-4356"],"issn-type":[{"value":"0163-4356","type":"print"}],"subject":[],"published":{"date-parts":[[2019,4]]}}}