{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:59:57Z","timestamp":1792040397218,"version":"4.4.0"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C0) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV &gt; 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p &lt; 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV \u2264 50th percentile. Similarly, patients with IPV &gt; 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p &lt; 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV \u2264 75th percentile. Multivariate analyses showed that high Tac IPV (&gt;50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.<\/jats:p>","DOI":"10.3390\/ph15121529","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T01:51:26Z","timestamp":1670550686000},"page":"1529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3412-7563","authenticated-orcid":false,"given":"Daniel N.","family":"Marco","sequence":"first","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4567-3682","authenticated-orcid":false,"given":"Mar\u00eda Queralt","family":"Salas","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Guti\u00e9rrez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Monge","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacy Service, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-0811","authenticated-orcid":false,"given":"Gisela","family":"Riu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacy Service, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Carcelero","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacy Service, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan Ram\u00f3n","family":"Roma","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacy Service, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noem\u00ed","family":"Llobet","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Arcarons","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Su\u00e1rez-Lled\u00f3","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Pedraza","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadna","family":"Domenech","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2534-9239","authenticated-orcid":false,"given":"Laura","family":"Rosi\u00f1ol","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Fern\u00e1ndez-Avil\u00e9s","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1lvaro","family":"Urbano-Isp\u00edzua","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Rovira","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merc\u00e8","family":"Brunet","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, Hospital Cl\u00ednic, IDIBAPS, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.7326\/M19-2936","article-title":"Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003\u20132007 Versus 2013\u20132017 Cohorts","volume":"172","author":"McDonald","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/nrclinonc.2014.102","article-title":"Current and emerging strategies for the prevention of graft-versus-host disease","volume":"11","author":"Choi","year":"2014","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e157","DOI":"10.1016\/S2352-3026(19)30256-X","article-title":"Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: Updated consensus recommendations of the European Society for Blood and Marrow Transplantation","volume":"7","author":"Penack","year":"2020","journal-title":"Lancet Haematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.bbmt.2005.12.034","article-title":"Thymoglobulin Prevents Chronic Graft-versus-Host Disease, Chronic Lung Dysfunction, and Late Transplant-Related Mortality: Long-Term Follow-Up of a Randomized Trial in Patients Undergoing Unrelated Donor Transplantation","volume":"12","author":"Bacigalupo","year":"2006","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1200\/JCO.2017.75.8177","article-title":"Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti\u2013T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease\u2013Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation","volume":"35","author":"Soiffer","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.bbmt.2008.03.005","article-title":"HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose, Posttransplantation Cyclophosphamide","volume":"14","author":"Luznik","year":"2008","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e132","DOI":"10.1016\/S2352-3026(18)30221-7","article-title":"Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: A randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)","volume":"6","author":"Reshef","year":"2019","journal-title":"Lancet Haematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1182\/blood-2019-124659","article-title":"Post-Transplantation Cyclophosphamide after Allogeneic Hematopoietic Stem Cell Transplantation: Results of the Prospective Randomized HOVON-96 Trial in Recipients of Matched Related and Unrelated Donors","volume":"134","author":"Meijer","year":"2019","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1097\/FTD.0000000000000640","article-title":"Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report","volume":"41","author":"Brunet","year":"2019","journal-title":"Ther. Drug Monit."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1080\/17425255.2019.1675635","article-title":"Tacrolimus in adult hematopoietic stem cell transplantation","volume":"15","author":"Gao","year":"2019","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S1083-8791(98)50005-5","article-title":"Relationship of tacrolimus (FK506) whole blood concentrations and efficacy and safety after HLA-identical sibling bone marrow transplantation","volume":"4","author":"Wingard","year":"1998","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1038\/sj.bmt.1702032","article-title":"Practical considerations in the use of tacrolimus for allogeneic marrow transplantation","volume":"24","author":"Przepiorka","year":"1999","journal-title":"Bone Marrow Transplant."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1182\/blood-2014-04-567164","article-title":"Tacrolimus\/sirolimus vs tacrolimus\/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT","volume":"124","author":"Cutler","year":"2014","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.1182\/blood.V108.11.2866.2866","article-title":"The Use of Sirolimus Combined with Tacrolimus and Low-Dose Methotrexate Is Effective in Preventing Graft-Versus-Host Disease after Unrelated Donor Hematopoietic Stem Cell Transplantation","volume":"108","author":"Nakamura","year":"2006","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/bmt.2015.323","article-title":"Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation","volume":"51","author":"Ganetsky","year":"2015","journal-title":"Bone Marrow Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.bbmt.2011.06.008","article-title":"Effect of Early Posttransplantation Tacrolimus Concentration on the Development of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donors","volume":"18","author":"Mori","year":"2011","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1038\/bmt.2009.327","article-title":"Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children","volume":"45","author":"Watanabe","year":"2009","journal-title":"Bone Marrow Transplant."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/phar.2480","article-title":"Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective","volume":"41","author":"Schumacher","year":"2020","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/cpt.1618","article-title":"Intrapatient Variability of Tacrolimus Exposure in Solid Organ Transplantation: A Novel Marker for Clinical Outcome","volume":"107","author":"Kuypers","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1111\/ajt.16002","article-title":"A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation","volume":"20","author":"Gonzales","year":"2020","journal-title":"Am. J. Transplant."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1097\/TP.0000000000001129","article-title":"High Intrapatient Tacrolimus Variability Is Associated With Worse Outcomes in Renal Transplantation Using a Low-Dose Tacrolimus Immunosuppressive Regime","volume":"101","author":"Whalen","year":"2017","journal-title":"Transplantation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.3748\/wjg.v24.i16.1795","article-title":"High tacrolimus intra-patient variability is associated with graft rejection, and de novo donor-specific antibodies occurrence after liver transplantation","volume":"24","author":"Danjoux","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1111\/ajt.15016","article-title":"High tacrolimus trough level variability is associated with rejections after heart transplant","volume":"18","author":"Gueta","year":"2018","journal-title":"Am. J. Transplant."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1182\/blood-2005-02-0509","article-title":"In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets","volume":"106","author":"Beilhack","year":"2005","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41409-018-0267-5","article-title":"Low mean post-transplantation tacrolimus levels in weeks 2\u20133 correlate with acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation from related and unrelated donors","volume":"54","author":"Hagen","year":"2018","journal-title":"Bone Marrow Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/s41409-021-01528-y","article-title":"Tacrolimus initial steady state level in post-transplant cyclophosphamide-based GvHD prophylaxis regimens","volume":"57","author":"Yao","year":"2021","journal-title":"Bone Marrow Transplant."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"619.e1","DOI":"10.1016\/j.jtct.2021.03.022","article-title":"High-Dose Cyclophosphamide and Tacrolimus as Graft-versus-Host Disease Prophylaxis for Matched and Mismatched Unrelated Donor Transplantation","volume":"27","author":"Pedraza","year":"2021","journal-title":"Transplant. Cell. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e260","DOI":"10.1016\/S1473-3099(19)30107-0","article-title":"Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)","volume":"19","author":"Ljungman","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1182\/blood.2019000956","article-title":"How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation","volume":"135","author":"Einsele","year":"2020","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.beha.2014.10.011","article-title":"Improved accuracy of acute graft-versus-host disease staging among multiple centers","volume":"27","author":"Levine","year":"2014","journal-title":"Best Pract. Res. Clin. Haematol."},{"key":"ref_31","first-page":"1","article-title":"Improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury","volume":"2","author":"Kellum","year":"2012","journal-title":"Kidney Int. Suppl."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1097\/TP.0b013e3181f24e8d","article-title":"Validation of Recently Proposed Consensus Criteria for Thrombotic Microangiopathy After Allogeneic Hematopoietic Stem-Cell Transplantation","volume":"90","author":"Cho","year":"2010","journal-title":"Transplantation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.blre.2014.11.001","article-title":"A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury","volume":"29","author":"Jodele","year":"2015","journal-title":"Blood Rev."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/12\/1529\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:36:56Z","timestamp":1760146616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/12\/1529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,9]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ph15121529"],"URL":"https:\/\/doi.org\/10.3390\/ph15121529","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,9]]}}}