{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:21:04Z","timestamp":1782843664166,"version":"3.54.5"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2008,4,30]],"date-time":"2008-04-30T00:00:00Z","timestamp":1209513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2008,10]]},"abstract":"<jats:sec><jats:label\/><jats:p> <jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003Ciclosporin is an immunosuppressant drug that is commonly used as prophylaxis against graft\u2010versus\u2010host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (SCT) in children.<\/jats:p><jats:p>\u2022\u2003Therapeutic drug monitoring is necessary because of its unpredictable absorption and narrow therapeutic window.<\/jats:p><jats:p>\u2022\u2003Data on the pharmacokinetics of ciclosporin and the relation between its systemic exposure, as reflected by the AUC (area\u2010under\u2010the\u2010curve), and the biological effect as GVHD prophylaxis are scarce in children after SCT.<\/jats:p><jats:p> <jats:bold>WHAT THIS STUDY ADDS<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003An adequate estimate of the systemic exposure of ciclosporin, following limiting sampling after intravenous and oral administration, can be obtained in children after SCT by determining the AUC using a two\u2010compartment pharmacokinetic model with lag time in combination with a limited sampling strategy.<\/jats:p><jats:p>\u2022\u2003Large interindividual variability in ciclosporin clearance was found, which was independent of body weight; this finding justifies a dosing strategy distinct from that per kg body weight.<\/jats:p><jats:p>\u2022\u2003Limited sampling modelling may serve as a tool to study the relationship between systemic exposure (\u223cAUC) and biological effects of ciclosporin, i.e. facilitation of engraftment, prevention of GVHD and avoidance of toxic effects of ciclosporin.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To develop a limited sampling strategy to determine ciclosporin systemic exposure [area\u2010under\u2010the\u2010curve(AUC)]. This is meant to be the first step in a future study of the relationship between AUC and the biological effects of ciclosporin.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>The pharmacokinetics of ciclosporin was investigated prospectively following stem cell transplantation (SCT) in 17 children, aged 1.8\u201316.1 years. Ciclosporin was given twice daily, intravenously over a short infusion of 2\u2003h duration during the early post\u2010SCT period, or orally later on, when oral medication was well tolerated. Parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. Individual empirical Bayes estimates of clearance and distribution volume were correlated with the demographic variables.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Pharmacokinetics was described adequately with a two\u2010compartment model with lag time (population estimates: CL\u2003=\u200311.3\u2003l\u2003h<jats:sup>\u22121<\/jats:sup>; <jats:italic>V<\/jats:italic><jats:sub>c<\/jats:sub>\u2003=\u200316.5\u2003l; <jats:italic>V<\/jats:italic><jats:sub>p<\/jats:sub>\u2003=\u200359.9\u2003l; <jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub> absorption\u2003=\u20030.78\u2003h, <jats:italic>t<\/jats:italic><jats:sub>lag<\/jats:sub>\u2003=\u20030.6\u2003h). The AUCs, determined for the combination of trough level with one time point between 2 and 3\u2003h after dosing, correlated very well with the reference AUC (<jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup>\u2003=\u20030.97). No correlation was found between clearance and distribution volume, and the demographic patient variables length, body weight, age and glomerular filtration rate.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>A two\u2010point limited sampling strategy, in combination with a Bayesian fitting procedure using the pharmacokinetic population model described, can adequately determine the AUC of ciclosporin. Since no correlation between clearance and body weight was found, dosing ciclosporin per\u2003kg bodyweight is not supported by the results of this study. We suggest starting with a fixed dose, followed by AUC determination and dose adjustment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2008.03217.x","type":"journal-article","created":{"date-parts":[[2008,4,30]],"date-time":"2008-04-30T09:59:03Z","timestamp":1209549543000},"page":"539-545","source":"Crossref","is-referenced-by-count":27,"title":["Ciclosporin kinetics in children after stem cell transplantation"],"prefix":"10.1111","volume":"66","author":[{"given":"A. J.","family":"Willemze","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. C.","family":"Cremers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. C.","family":"Schoemaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. C.","family":"Lankester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Den Hartigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Burggraaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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