{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:41:52Z","timestamp":1784266912491,"version":"3.55.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:sec><jats:title>Background:<\/jats:title><jats:p>Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially because of inconsistencies in sirolimus exposure\u2013response relationships.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary health care system from 2008 to 2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to simulate sirolimus concentrations, and (3) characterize the exposure\u2013response relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors determined relationships between sirolimus exposure and adverse events (AEs) (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal function) and the composite efficacy end point of graft loss or rejection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>The developed 2-compartment population PK model showed appropriate goodness of fit. In a late-phase (&gt;12 months), postrenal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (<jats:italic toggle=\"yes\">P<\/jats:italic>= 0.018) and decline in renal function (<jats:italic toggle=\"yes\">P<\/jats:italic>= 0.006), respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function. However, the method was limited in its assessment of other AEs. To better evaluate sirolimus exposure\u2013response relationships, the method should be applied to a larger sample of newly transplanted patients with a higher propensity toward AEs or efficacy failure.<\/jats:p><\/jats:sec>","DOI":"10.1097\/ftd.0000000000000313","type":"journal-article","created":{"date-parts":[[2016,6,2]],"date-time":"2016-06-02T13:50:51Z","timestamp":1464875451000},"page":"600-606","source":"Crossref","is-referenced-by-count":13,"title":["Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure\u2013Response Relationships in Renal Transplant Patients"],"prefix":"10.1097","volume":"38","author":[{"given":"Kanecia O.","family":"Zimmerman","sequence":"first","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"},{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huali","family":"Wu","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"},{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey T.","family":"Guptill","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Hill","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"},{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uptal D.","family":"Patel","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"},{"name":"Pediatrics and"},{"name":"Medicine, Duke University School of Medicine, Durham, North Carolina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Ku","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"},{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hornik","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"},{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Office of Generic Drugs, US Food and Drug Administration, Silver Spring, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Melloni","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cohen-Wolkowiez","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina;"},{"name":"Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20230814","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1001\/jama.1975.03240180019013","article-title":"Report of the committee for the assessment of biometric aspects of controlled trials of hypoglycemic agents","volume":"231","year":"1975","journal-title":"JAMA"},{"key":"R2-20230814","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2165\/00002018-200528020-00006","article-title":"Benefit-risk assessment of sirolimus in renal transplantation","volume":"28","author":"Kuypers","year":"2005","journal-title":"Drug Saf."},{"key":"R4-20230814","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1034\/j.1399-0012.2000.140201.x","article-title":"Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity","volume":"14","author":"Kahan","year":"2000","journal-title":"Clin Transplant."},{"key":"R5-20230814","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/(SICI)1099-081X(199907)20:5<249::AID-BDD181>3.0.CO;2-9","article-title":"Conversion from liquid to solid rapamycin formulations in stable renal allograft transplant recipients","volume":"20","author":"Kelly","year":"1999","journal-title":"Biopharm Drug Dispos."},{"issue":"suppl B","key":"R6-20230814","doi-asserted-by":"crossref","first-page":"B101","DOI":"10.1016\/S0149-2918(00)89027-X","article-title":"Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus","volume":"22","author":"MacDonald","year":"2000","journal-title":"Clin Ther."},{"key":"R7-20230814","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1097\/00007890-200101270-00019","article-title":"A worldwide, phase III, randomized, controlled, safety and efficacy study of a sirolimus\/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts","volume":"71","author":"MacDonald","year":"2001","journal-title":"Transplantation"},{"key":"R8-20230814","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1097\/00007890-199911270-00016","article-title":"Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group","volume":"68","author":"Kahan","year":"1999","journal-title":"Transplantation"},{"key":"R9-20230814","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1111\/j.1600-6143.2005.01193.x","article-title":"Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study","volume":"6","author":"Vitko","year":"2006","journal-title":"Am J Transplant."},{"key":"R10-20230814","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1399-0012.2004.00116.x","article-title":"Observations regarding the use of sirolimus and tacrolimus in high-risk cadaveric renal transplantation","volume":"18","author":"Lo","year":"2004","journal-title":"Clin Transplant."},{"key":"R11-20230814","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.transproceed.2011.11.059","article-title":"Sirolimus-induced pneumonitis after renal transplantation: a single-center experience","volume":"44","author":"Lee","year":"2012","journal-title":"Transplant Proc."},{"key":"R12-20230814","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1093\/ndt\/gfm420","article-title":"Pneumonitis associated with sirolimus: clinical characteristics, risk factors and outcome\u2013a single-centre experience and review of the literature","volume":"22","author":"Weiner","year":"2007","journal-title":"Nephrol Dial Transplant."},{"key":"R13-20230814","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.cmpb.2010.04.018","article-title":"Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM","volume":"101","author":"Keizer","year":"2011","journal-title":"Comput Methods Programs Biomed."},{"key":"R14-20230814","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.cmpb.2003.11.003","article-title":"Perl-speaks-NONMEM (PsN)\u2013a Perl module for NONMEM related programming","volume":"75","author":"Lindbom","year":"2004","journal-title":"Comput Methods Programs Biomed."},{"key":"R15-20230814","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0169-2607(98)00067-4","article-title":"Xpose\u2013an S-PLUS based population pharmacokinetic\/pharmacodynamic model building aid for NONMEM","volume":"58","author":"Jonsson","year":"1999","journal-title":"Comput Methods Programs Biomed."},{"key":"R16-20230814","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1177\/0091270010390040","article-title":"Standardized visual predictive check versus visual predictive check for model evaluation","volume":"52","author":"Wang","year":"2012","journal-title":"J Clin Pharmacol."},{"key":"R17-20230814","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S0009-9236(97)90192-2","article-title":"Population pharmacokinetics of sirolimus in kidney transplant patients","volume":"61","author":"Ferron","year":"1997","journal-title":"Clin Pharmacol Ther."},{"key":"R18-20230814","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.2165\/00003088-200645110-00007","article-title":"Sirolimus population pharmacokinetic\/pharmacogenetic analysis and Bayesian modelling in kidney transplant recipients","volume":"45","author":"Djebli","year":"2006","journal-title":"Clin Pharmacokinet."},{"key":"R19-20230814","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1365-2125.2009.03392.x","article-title":"Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients","volume":"68","author":"Jiao","year":"2009","journal-title":"Br J Clin Pharmacol."},{"key":"R20-20230814","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1177\/009127009903901107","article-title":"The effect of a high-fat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin)","volume":"39","author":"Zimmerman","year":"1999","journal-title":"J Clin Pharmacol."},{"key":"R21-20230814","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1208\/aapsj060428","article-title":"Exposure-response relationships and drug interactions of sirolimus","volume":"6","author":"Zimmerman","year":"2004","journal-title":"AAPS J."},{"key":"R22-20230814","doi-asserted-by":"crossref","first-page":"130S","DOI":"10.1002\/j.1875-9114.1991.tb02643.x","article-title":"Recent advances in cyclosporine pharmacokinetics","volume":"11","author":"Yee","year":"1991","journal-title":"Pharmacotherapy"},{"key":"R23-20230814","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1097\/00007890-199311000-00029","article-title":"Blood distribution of rapamycin","volume":"56","author":"Yatscoff","year":"1993","journal-title":"Transplantation"},{"key":"R25-20230814","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/0006-2952(95)00192-3","article-title":"Age but not gender selectively affects expression of individual cytochrome P450 proteins in human liver","volume":"50","author":"George","year":"1995","journal-title":"Biochem Pharmacol."},{"key":"R26-20230814","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1093\/ndt\/gfi336","article-title":"Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: benefits and risks","volume":"21","author":"Diekmann","year":"2006","journal-title":"Nephrol Dial Transplant."},{"key":"R27-20230814","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1016\/j.transproceed.2009.07.094","article-title":"Conversion to sirolimus for chronic allograft nephropathy and calcineurin inhibitor toxicity and the adverse effects of sirolimus after conversion","volume":"41","author":"Sayin","year":"2009","journal-title":"Transplant Proc."},{"key":"R28-20230814","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.trim.2006.10.001","article-title":"The aetiology and pathogenesis of chronic allograft nephropathy","volume":"16","author":"Yates","year":"2006","journal-title":"Transpl Immunol."},{"key":"R29-20230814","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1097\/00007890-199502000-00006","article-title":"Incidence, determinants, and consequences of subclinical noncompliance with immunosuppressive therapy in renal transplant recipients","volume":"59","author":"De Geest","year":"1995","journal-title":"Transplantation"},{"key":"R30-20230814","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1097\/00007890-199609150-00010","article-title":"Variable oral absorption of cyclosporine. A biopharmaceutical risk factor for chronic renal allograft rejection","volume":"62","author":"Kahan","year":"1996","journal-title":"Transplantation"},{"key":"R31-20230814","first-page":"552","article-title":"Effect of early cyclosporine levels on kidney allograft rejection","volume":"11","author":"Johnson","year":"1997","journal-title":"Clin Transplant."},{"key":"R32-20230814","doi-asserted-by":"crossref","first-page":"326","DOI":"10.2215\/CJN.03751106","article-title":"High sirolimus levels may induce focal segmental glomerulosclerosis de novo","volume":"2","author":"Letavernier","year":"2007","journal-title":"Clin J Am Soc Nephrol."},{"key":"R33-20230814","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1046\/j.1523-1755.2001.00460.x","article-title":"Rapamycin in transplantation: a review of the evidence","volume":"59","author":"Saunders","year":"2001","journal-title":"Kidney Int."},{"key":"R34-20230814","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1007\/s11096-012-9614-6","article-title":"Short term impact of guidelines on vancomycin dosing and therapeutic drug monitoring","volume":"34","author":"Swartling","year":"2012","journal-title":"Int J Clin Pharm."},{"key":"R35-20230814","doi-asserted-by":"crossref","first-page":"374","DOI":"10.2215\/CJN.03791106","article-title":"Therapeutic monitoring of calcineurin inhibitors for the nephrologist","volume":"2","author":"Schiff","year":"2007","journal-title":"Clin J Am Soc Nephrol."},{"key":"R36-20230814","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/ki.1996.28","article-title":"The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients","volume":"49","author":"Murgia","year":"1996","journal-title":"Kidney Int."}],"container-title":["Therapeutic Drug Monitoring"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/00007691-201610000-00007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T09:09:23Z","timestamp":1718615363000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/00007691-201610000-00007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016]]}},"URL":"https:\/\/doi.org\/10.1097\/ftd.0000000000000313","relation":{},"ISSN":["0163-4356"],"issn-type":[{"value":"0163-4356","type":"print"}],"subject":[],"published":{"date-parts":[[2016,10]]}}}