{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T06:43:12Z","timestamp":1779000192493,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T00:00:00Z","timestamp":1728604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chiesi (Chiesi Farmaceutici S. p. A. Via Palermo 26\/A 43122 Parma, Italy) (project-related support)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: There is a narrow therapeutic window for immunosuppression using calcineurin inhibitors. Drug trough levels do not reflect immunosuppression and should be replaced by pharmacodynamic monitoring. This prospective cohort study was designed to evaluate the effect of an extended-release formulation of tacrolimus (LCP Tac) on the nuclear factor of activated T cell-regulated gene expression (NFAT-RGE). Methods: The expression of interleukin-2, interferon-\u03b3, granulocyte-macrophage colony-stimulating factor, and three reference genes was measured. Samples from 23 patients at defined time points in the first year after liver transplantation were analyzed using a droplet digital polymerase chain reaction. Results: All samples were within the targeted trough levels of LCP Tac, and their LCP Tac peak levels and residual NFAT-RGE showed a strong inverse correlation (r = \u22120.8). Most importantly, there was an individual immunosuppressive response to the LCP Tac. The mean individual trough effect of LCP Tac on the three target genes when all time points were pooled was 33% (26\u201356%) in patients without infection and 81% (53\u201395%) in those with infection (p &lt; 0.011). The mean individual peak effect was 48% (44\u201364%) in patients without infection and 91% (90\u201394%) in those with infection (p &lt; 0.001). Conclusions: Thus, tailored immunosuppression based on residual NFAT-RGE could prevent infections associated with over-immunosuppression early after liver transplantation.<\/jats:p>","DOI":"10.3390\/pharmaceutics16101317","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T03:53:47Z","timestamp":1728618827000},"page":"1317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Use of Nuclear Factor of Activated T Cell-Regulated Gene Expression for Monitoring Immunosuppression with Extended-Release Tacrolimus after Liver Transplantation\u2014A Proof of Concept"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2341-6386","authenticated-orcid":false,"given":"Judith","family":"Kahn","sequence":"first","affiliation":[{"name":"Division of General, Visceral, and Transplant Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4914-9880","authenticated-orcid":false,"given":"Eva Maria","family":"Matzhold","sequence":"additional","affiliation":[{"name":"Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3271-3836","authenticated-orcid":false,"given":"Peter","family":"Schlenke","sequence":"additional","affiliation":[{"name":"Department of Blood Group Serology and Transfusion Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4192-6155","authenticated-orcid":false,"given":"Peter","family":"Schemmer","sequence":"additional","affiliation":[{"name":"Division of General, Visceral, and Transplant Surgery, Department of Surgery, Medical University of Graz, 8036 Graz, Austria"},{"name":"Bern Visceral Surgery & Pancreas Clinic Switzerland, Hirslanden Hospital Beau-Site, 3013 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1097\/TP.0000000000004153","article-title":"Integrated Immunologic Monitoring in Solid Organ Transplantation: The Road Toward Torque Teno Virus-guided Immunosuppression","volume":"106","author":"Jaksch","year":"2022","journal-title":"Transplantation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e13495","DOI":"10.1111\/tid.13495","article-title":"Functional immune monitoring of BK Virus and donor-specific T-cell effector immune responses to guide treatment decision-making after kidney transplantation; an illustrative case report and literature review","volume":"23","author":"Lepore","year":"2021","journal-title":"Transpl. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1006\/jmbi.1999.2684","article-title":"Recognition of NFATp\/AP-1 composite elements within genes induced upon the activation of immune cells","volume":"288","author":"Kel","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Meuer, S., Wittwer, C., and Nakagawara, K. (2001). Development of quantitative RT-PCR tests for the expression of cytokine genes on the LightCycler. Rapid Cycle Real-Time PCR: Methods and Applications, Springer.","DOI":"10.1007\/978-3-642-59524-0"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/ndt\/gfn556","article-title":"Pharmacodynamic monitoring of calcineurin inhibitor therapy: Is there a clinical benefit?","volume":"24","author":"Sommerer","year":"2009","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"von Einsiedel, J., Th\u00f6lking, G., Wilms, C., Vorona, E., Bokemeyer, A., Schmidt, H.H., Kabar, I., and H\u00fcsing-Kabar, A. (2020). Conversion from Standard-Release Tacrolimus to MeltDose\u00ae Tacrolimus (LCPT) Improves Renal Function after Liver Transplantation. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061654"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/phar.2300","article-title":"Tacrolimus Concentration-to-Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes","volume":"39","author":"Bartlett","year":"2019","journal-title":"Pharmacotherapy"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2016). EASL clinical practice guidelines: Liver transplantation. J. Hepatol., 64, 433\u2013485.","DOI":"10.1016\/j.jhep.2015.10.006"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1097\/01.TP.0000109260.00094.01","article-title":"Monitoring of NFAT-regulated gene expression in the peripheral blood of allograft recipients: A novel perspective toward individually optimized drug doses of cyclosporine A","volume":"77","author":"Giese","year":"2004","journal-title":"Transplantation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/ajt.13935","article-title":"A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study","volume":"17","author":"Tremblay","year":"2017","journal-title":"Am. J. Transplant."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"93","DOI":"10.5414\/CN108893","article-title":"Correlation between pharmacokinetics of tacrolimus and pharmacodynamics on NFAT-regulated gene expression in stable kidney transplant recipients","volume":"87","author":"Keller","year":"2017","journal-title":"Clin. Nephrol."},{"key":"ref_12","first-page":"1000","article-title":"Monitoring of NFAT-regulated gene-expression for safe tapering of CNI immunosuppression in BK virus positive renal transplant patients","volume":"18","author":"Sommerer","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1097\/TP.0000000000001973","article-title":"Improved Pulse Wave Velocity and Renal Function in Individualized Calcineurin Inhibitor Treatment by Immunomonitoring: The Randomized Controlled Calcineurin Inhibitor-Sparing Trial","volume":"102","author":"Sommerer","year":"2018","journal-title":"Transplantation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.5414\/CN108623","article-title":"Monitoring of calcineurin inhibitors by NFAT-regulated gene expression in de novo renal allograft recipients","volume":"84","author":"Sommerer","year":"2015","journal-title":"Clin. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1097\/FTD.0b013e318237e33c","article-title":"Pharmacodynamic monitoring of cyclosporin A reveals risk of opportunistic infections and malignancies in renal transplant recipients 65 years and older","volume":"33","author":"Sommerer","year":"2011","journal-title":"Ther. Drug Monit."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1097\/01.tp.0000243358.75863.57","article-title":"Pharmacodynamic monitoring of cyclosporine a in renal allograft recipients shows a quantitative relationship between immunosuppression and the occurrence of recurrent infections and malignancies","volume":"82","author":"Sommerer","year":"2006","journal-title":"Transplantation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1097\/01.tp.0000296824.58884.55","article-title":"Ciclosporin A tapering monitored by NFAT-regulated gene expression: A new concept of individual immunosuppression","volume":"85","author":"Sommerer","year":"2008","journal-title":"Transplantation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/j.1399-0012.2008.00819.x","article-title":"Pharmacodynamic immune monitoring of NFAT-regulated genes predicts skin cancer in elderly long-term renal transplant recipients","volume":"22","author":"Sommerer","year":"2008","journal-title":"Clin. Transplant."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/j.1600-051X.2011.01773.x","article-title":"Cyclosporine-induced gingivalover growth correlates with NFAT-regulated gene expression: A pilot study","volume":"38","author":"Dannewitz","year":"2011","journal-title":"J. Clin. Periodontol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1111\/j.1399-3046.2010.01354.x","article-title":"Pharmacodynamic monitoring of cyclosporine A by NFAT-regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients","volume":"14","author":"Billing","year":"2010","journal-title":"Pediatr. Transplant."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1399-3046.2012.01660.x","article-title":"Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients","volume":"16","author":"Billing","year":"2012","journal-title":"Pediatr. Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/lt.22254","article-title":"Immunomonitoring of nuclear factor of activated T cells-regulated gene expression: The first clinical trial in liver allograft recipients","volume":"17","author":"Zahn","year":"2011","journal-title":"Liver Transplant."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/FTD.0b013e318210e6d0","article-title":"Monitoring of nuclear factor of activated T-cell regulated gene expression in de novo and long-term liver transplant recipients treated with cyclosporine A","volume":"33","author":"Herden","year":"2011","journal-title":"Ther. Drug Monit."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.12659\/AOT.889809","article-title":"Pharmacodynamic monitoring of nuclear factor of activated T-cell regulated gene expression in liver allograft recipients on immunosuppressive therapy with calcineurin inhibitor in the course of time and correlation with acute rejection episodes\u2014A prospective study","volume":"19","author":"Zahn","year":"2014","journal-title":"Ann. Transplant."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/tid.12206","article-title":"Reduced residual gene expression of nuclear factor of activated T-cells-regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation","volume":"16","author":"Steinebrunner","year":"2014","journal-title":"Transpl. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1111\/j.1432-2277.2007.00552.x","article-title":"Pharmacodynamic cyclosporine A-monitoring: Relation of gene expression in lymphocytes to cyclosporine blood levels in cardiac allograft recipients","volume":"20","author":"Konstandin","year":"2007","journal-title":"Transpl. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1097\/TP.0b013e3181dc13b6","article-title":"Individualized monitoring of nuclear factor of activated T-cells-regulated gene expression in FK506-treated kidney transplant recipients","volume":"89","author":"Sommerer","year":"2010","journal-title":"Transplantation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1097\/FTD.0b013e318226dac7","article-title":"Pharmacodnamic disparities in tacrolimus treated patients developing CMV viremia","volume":"33","author":"Sommerer","year":"2011","journal-title":"Ther. Drug Monit."},{"key":"ref_29","first-page":"19","article-title":"Detection of patients on increased risk of BKV replication by NFAT-regulated gene expression","volume":"28","author":"Sommerer","year":"2015","journal-title":"Transpl. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2494","DOI":"10.1111\/bcp.13367","article-title":"NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation","volume":"83","author":"Bremer","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3851","DOI":"10.1111\/bcp.14794","article-title":"Monitoring of gene expression in tacrolimus-treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study","volume":"87","author":"Sommerer","year":"2021","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e369","DOI":"10.1097\/TXD.0000000000000810","article-title":"Nuclear Factor of Activated T Cell-regulated Cytokine Gene Expression for Adjustment of Tacrolimus in Kidney Transplant Recipients: A Randomized Controlled Pilot Trial","volume":"4","author":"Webber","year":"2018","journal-title":"Transplant. Direct."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/liv.14339","article-title":"Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients","volume":"40","author":"Ruiz","year":"2020","journal-title":"Liver Int."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/10\/1317\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:10:59Z","timestamp":1760112659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/10\/1317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,11]]},"references-count":33,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["pharmaceutics16101317"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16101317","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,11]]}}}