{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:39:13Z","timestamp":1793255953516,"version":"4.5.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,12]]},"abstract":"\n Background:<\/jats:title>\n Routine therapeutic drug monitoring (TDM) relies heavily on measuring trough drug concentrations. Trough concentrations are affected not only by drug bioavailability and clearance, but also by various patient and disease factors and the volume of distribution. This often makes interpreting differences in drug exposure from trough data challenging. This study aimed to combine the advantages of top-down analysis of therapeutic drug monitoring data with bottom-up physiologically-based pharmacokinetic (PBPK) modeling to investigate the effect of declining renal function in chronic kidney disease (CKD) on the nonrenal intrinsic metabolic clearance (CL<\/jats:italic>\n \n int\n <\/jats:sub>) of tacrolimus as a case example.<\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n Data on biochemistry, demographics, and kidney function, along with 1167 tacrolimus trough concentrations for 40 renal transplant patients, were collected from the Salford Royal Hospital's database. A reduced PBPK model was developed to estimate CL<\/jats:italic>\n \n int\n <\/jats:sub> for each patient. Personalized unbound fractions, blood-to-plasma ratios, and drug affinities for various tissues were used as priors to estimate the apparent volume of distribution. Kidney function based on the estimated glomerular filtration rate (eGFR<\/jats:italic>) was assessed as a covariate for CL<\/jats:italic>\n \n int\n <\/jats:sub> using the stochastic approximation of expectation and maximization method.<\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n At baseline, the median (interquartile range) eGFR<\/jats:italic> was 45 (34.5\u201355.5) mL\/min\/1.73 m2<\/jats:sup>. A significant but weak correlation was observed between tacrolimus CL<\/jats:italic>\n \n int\n <\/jats:sub> and eGFR<\/jats:italic> (r = 0.2, P<\/jats:italic> < 0.001). The CL<\/jats:italic>\n \n int\n <\/jats:sub> declined gradually (up to 36%) with CKD progression. Tacrolimus CL<\/jats:italic>\n \n int\n <\/jats:sub> did not differ significantly between stable and failing transplant patients.<\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n Kidney function deterioration in CKD can affect nonrenal CL<\/jats:italic>\n \n int\n <\/jats:sub> for drugs that undergo extensive hepatic metabolism, such as tacrolimus, with critical implications in clinical practice. This study demonstrates the advantages of combining prior system information (via PBPK) to investigate covariate effects in sparse real-world datasets.<\/jats:p>\n <\/jats:sec>","DOI":"10.1097\/ftd.0000000000001108","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T18:00:08Z","timestamp":1686765608000},"page":"743-753","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":4,"title":["Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease"],"prefix":"10.1097","volume":"45","author":[{"given":"Eman","family":"El-Khateeb","sequence":"first","affiliation":[{"name":"Certara UK Limited (Simcyp Division), Sheffield, United Kingdom;"},{"name":"Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajkumar","family":"Chinnadurai","sequence":"additional","affiliation":[{"name":"Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom;"},{"name":"Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jokha","family":"Al Qassabi","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom;"},{"name":"University of Technology and Applied Sciences, Muscat, Oman; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Scotcher","sequence":"additional","affiliation":[{"name":"Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam S.","family":"Darwich","sequence":"additional","affiliation":[{"name":"Logistics and Informatics in Health Care, KTH Royal Institute of Technology, Stockholm, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip A.","family":"Kalra","sequence":"additional","affiliation":[{"name":"Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom;"},{"name":"Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3917-844X","authenticated-orcid":false,"given":"Amin","family":"Rostami-Hodjegan","sequence":"additional","affiliation":[{"name":"Certara UK Limited (Simcyp Division), Sheffield, United Kingdom;"},{"name":"Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"R2-20250603","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1080\/10428194.2018.1485907","article-title":"Imatinib trough levels: a potential biomarker to predict cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia","volume":"60","author":"Natarajan","year":"2019","journal-title":"Leuk Lymphoma"},{"key":"R3-20250603","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/psp4.12492","article-title":"Bayesian data assimilation to support informed decision making in individualized chemotherapy","volume":"9","author":"Maier","year":"2020","journal-title":"CPT Pharmacometrics Syst Pharmacol."},{"key":"R4-20250603","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/cpt.337","article-title":"Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4\/5","volume":"100","author":"Yoshida","year":"2016","journal-title":"Clin Pharmacol Ther."},{"key":"R5-20250603","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1007\/s00228-014-1709-7","article-title":"Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins","volume":"70","author":"Barnes","year":"2014","journal-title":"Eur J Clin Pharmacol."},{"key":"R6-20250603","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/ki.2013.399","article-title":"Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport","volume":"85","author":"Yeung","year":"2014","journal-title":"Kidney Int."},{"key":"R7-20250603","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1517\/17425255.4.8.1065","article-title":"The effect of chronic renal failure on drug metabolism and transport","volume":"4","author":"Dreisbach","year":"2008","journal-title":"Expert Opin Drug Metab Toxicol."},{"key":"R8-20250603","doi-asserted-by":"crossref","first-page":"18","DOI":"10.2165\/00003088-198400091-00003","article-title":"Alteration of drug-protein binding in renal disease","volume":"9","author":"Reidenberg","year":"1984","journal-title":"Pharmacokinet"},{"key":"R9-20250603","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/cpt.2642","article-title":"Effect of chronic kidney disease on the renal secretion via organic anion transporters 1\/3: implications for physiologically\u2010based pharmacokinetic modeling and dose adjustment","volume":"112","author":"Tan","year":"2022","journal-title":"Clin Pharmacol Ther."},{"key":"R10-20250603","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2165\/00003088-199529060-00003","article-title":"Clinical pharmacokinetics of tacrolimus","volume":"29","author":"Venkataramanan","year":"1995","journal-title":"Clin Pharmacokinet."},{"key":"R11-20250603","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0009-9236(95)90153-1","article-title":"Pharmacokinetics of tacrolimus in liver transplant patients","volume":"57","author":"Jusko","year":"1995","journal-title":"Clin Pharmacol Ther."},{"key":"R12-20250603","doi-asserted-by":"crossref","first-page":"105237","DOI":"10.1016\/j.ejps.2020.105237","article-title":"Systematic external evaluation of published population pharmacokinetic models for tacrolimus in adult liver transplant recipients","volume":"145","author":"Cai","year":"2020","journal-title":"Eur J Pharm Sci."},{"key":"R13-20250603","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1111\/bcp.12830","article-title":"External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients","volume":"81","author":"Zhao","year":"2016","journal-title":"Br J Clin Pharmacol."},{"key":"R14-20250603","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00228-013-1584-7","article-title":"Importance of hematocrit for a tacrolimus target concentration strategy","volume":"70","author":"St\u00f8rset","year":"2014","journal-title":"Eur J Clin Pharmacol."},{"key":"R15-20250603","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1093\/ndt\/16.9.1905","article-title":"Low tacrolimus concentrations and increased risk of early acute rejection in adult renal transplantation","volume":"16","author":"Staatz","year":"2001","journal-title":"Nephrol Dial Transpl."},{"key":"R16-20250603","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1097\/00007890-199402270-00008","article-title":"FK506 trough levels in whole blood and plasma in liver transplant recipients. Correlation with clinical events and side effects","volume":"57","author":"B\u00e4ckman","year":"1994","journal-title":"Transplantation"},{"key":"R17-20250603","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1111\/tri.12155","article-title":"Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics","volume":"26","author":"Israni","year":"2013","journal-title":"Transpl Int."},{"key":"R18-20250603","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/jcpt.12396","article-title":"Population pharmacokinetics of tacrolimus in Thai kidney transplant patients: comparison with similar data from other populations","volume":"41","author":"Vadcharavivad","year":"2016","journal-title":"J Clin Pharm Ther."},{"key":"R19-20250603","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s13318-018-0525-3","article-title":"Population pharmacokinetic analysis of immediate-release oral tacrolimus co-administered with mycophenolate mofetil in corticosteroid-free adult kidney transplant recipients","volume":"44","author":"Rong","year":"2019","journal-title":"Eur J Drug Metab Pharmacokinet."},{"key":"R20-20250603","doi-asserted-by":"crossref","first-page":"3176","DOI":"10.1093\/ndt\/gfr003","article-title":"Introduction of the CKD-EPI equation to estimate glomerular filtration rate in a Caucasian population","volume":"26","author":"van den Brand","year":"2011","journal-title":"Nephrol Dial Transpl."},{"key":"R22-20250603","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1124\/dmd.106.013359","article-title":"Misuse of the well-stirred model of hepatic drug clearance: fig. 1","volume":"35","author":"Yang","year":"2007","journal-title":"Drug Metab Dispos."},{"key":"R23-20250603","doi-asserted-by":"crossref","first-page":"7283","DOI":"10.3390\/app10207283","article-title":"Predicting intestinal and hepatic first-pass metabolism of orally administered testosterone undecanoate","volume":"10","author":"Zgair","year":"2020","journal-title":"Appl Sci."},{"key":"R24-20250603","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/psp4.12392","article-title":"A theoretical physiologically-based pharmacokinetic approach to ascertain covariates explaining the large interpatient variability in tacrolimus disposition","volume":"8","author":"Emoto","year":"2019","journal-title":"CPT Pharmacometrics Syst Pharmacol."},{"key":"R25-20250603","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1124\/dmd.110.032649","article-title":"Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data","volume":"38","author":"Gertz","year":"2010","journal-title":"Drug Metab Dispos."},{"key":"R26-20250603","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/j.1365-2125.1981.tb01304.x","article-title":"Measurement of the renal clearance of drugs","volume":"12","author":"Tucker","year":"1981","journal-title":"Br J Clin Pharmacol."},{"key":"R27-20250603","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0090-9556(24)15298-1","article-title":"The disposition of 14C-labeled tacrolimus after intravenous and oral administration in healthy human subjects","volume":"27","author":"M\u00f6ller","year":"1999","journal-title":"Drug Metab Dispos."},{"key":"R28-20250603","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S1056-8719(02)00158-2","article-title":"Validation of methods to study the distribution and protein binding of tacrolimus in human blood","volume":"46","author":"Zahir","year":"2001","journal-title":"J Pharmacol Toxicol Methods"},{"key":"R30-20250603","doi-asserted-by":"crossref","first-page":"204","DOI":"10.4097\/kja.21085","article-title":"Interpretation of volume kinetics in terms of pharmacokinetic principles","volume":"74","author":"Choi","year":"2021","journal-title":"Korean J Anesthesiol."},{"key":"R34-20250603","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1016\/j.transproceed.2004.04.097","article-title":"Effect of hematocrit on pharmacokinetics of tacrolimus in adult living donor liver transplant recipients","volume":"36","author":"Minematsu","year":"2004","journal-title":"Transpl Proc."},{"key":"R35-20250603","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0146-6453(03)00002-2","article-title":"Basic anatomical and physiological data for use in radiological protection: reference values","volume":"32","author":"Valentin","year":"2002","journal-title":"Ann ICRP"},{"key":"R36-20250603","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1002\/jps.20322","article-title":"Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases","volume":"94","author":"Rodgers","year":"2005","journal-title":"J Pharm Sci."},{"key":"R37-20250603","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1007\/s11095-006-9210-3","article-title":"Mechanistic approaches to volume of distribution predictions: understanding the processes","volume":"24","author":"Rodgers","year":"2007","journal-title":"Pharm Res."},{"key":"R38-20250603","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1177\/000456329803500201","article-title":"Therapeutic monitoring of tacrolimus","volume":"35","author":"Trull","year":"1998","journal-title":"Ann Clin Biochem."},{"key":"R39-20250603","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1111\/bcp.13952","article-title":"Population pharmacokinetics of immediate- and prolonged-release tacrolimus formulations in liver, kidney and heart transplant recipients","volume":"85","author":"Lu","year":"2019","journal-title":"Br J Clin Pharmacol."},{"key":"R41-20250603","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/clpt.2014.55","article-title":"Identification of the effect of multiple polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid using a population-modeling approach","volume":"96","author":"Tsamandouras","year":"2014","journal-title":"Clin Pharmacol Ther."},{"key":"R42-20250603","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1002\/j.1552-4604.1994.tb02052.x","article-title":"Pharmacokinetics of FK506 after intravenous and oral administration in patients awaiting renal transplantation","volume":"34","author":"Gruber","year":"1994","journal-title":"J Clin Pharmacol."},{"key":"R43-20250603","doi-asserted-by":"crossref","first-page":"182","DOI":"10.21608\/aprh.2019.14237.1087","article-title":"Pharmacokinetics of tacrolimus in Egyptian liver transplant recipients: role of the classic co-variables","volume":"3","author":"Ebid","year":"2019","journal-title":"J Adv Pharm Res."},{"key":"R44-20250603","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/bcp.12234","article-title":"Combining the \u201cbottom up\u201dand \u201ctop down\u201dapproaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data","volume":"79","author":"Tsamandouras","year":"2015","journal-title":"Br J Clin Pharmacol Br J Clin Pharmacol."},{"key":"R45-20250603","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1097\/01.jcp.0000106221.36344.4d","article-title":"Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients","volume":"24","author":"Rostami-Hodjegan","year":"2004","journal-title":"J Clin Psychopharmacol."},{"key":"R46-20250603","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.2042-7158.1994.tb03752.x","article-title":"Distribution and protein binding of FK506, a potent immunosuppressive macrolide lactone, in human blood and its uptake by erythrocytes","volume":"46","author":"Nagase","year":"2011","journal-title":"J Pharm Pharmacol."},{"key":"R47-20250603","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.transproceed.2015.12.096","article-title":"Correlation of hematocrit and tacrolimus level in liver transplant recipients","volume":"48","author":"Limsrichamrern","year":"2016","journal-title":"Transpl Proc."},{"key":"R48-20250603","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1093\/ajhp\/52.14.1521","article-title":"Tacrolimus: a new immunosuppressive agent","volume":"52","author":"Kelly","year":"1995","journal-title":"Am J Health Syst Pharm."}],"container-title":["Therapeutic Drug Monitoring"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/FTD.0000000000001108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T17:12:32Z","timestamp":1748970752000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/FTD.0000000000001108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,13]]},"references-count":41,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023]]}},"URL":"https:\/\/doi.org\/10.1097\/ftd.0000000000001108","relation":{},"ISSN":["0163-4356"],"issn-type":[{"value":"0163-4356","type":"print"}],"subject":[],"published":{"date-parts":[[2023,6,13]]},"assertion":[{"value":"2023-01-11","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-23","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}