{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:13:31Z","timestamp":1791476011488,"version":"4.3.4"},"reference-count":25,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2008,8,15]],"date-time":"2008-08-15T00:00:00Z","timestamp":1218758400000},"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":[[2008,12]]},"abstract":"<jats:sec><jats:label\/><jats:p> <jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003The cytotoxic effects of 6\u2010mercaptopurine (6\u2010MP) were found to be due to drug\u2010derived intracellular metabolites (mainly 6\u2010thioguanine nucleotides and to some extent 6\u2010methylmercaptopurine nucleotides) rather than the drug itself.<\/jats:p><jats:p>\u2022\u2003Current empirical dosing methods for oral 6\u2010MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome.<\/jats:p><jats:p> <jats:bold>WHAT THIS STUDY ADDS<\/jats:bold> <\/jats:p><jats:p>\u2022\u2003The first population pharmacokinetic model has been developed for 6\u2010MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed.<\/jats:p><jats:p>\u2022\u2003The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates.<\/jats:p><jats:p>\u2022\u2003The developed model offers a more rational dosing approach for 6\u2010MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To investigate the population pharmacokinetics of 6\u2010mercaptopurine (6\u2010MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Data were collected prospectively from 19 paediatric patients with ALL (<jats:italic>n<\/jats:italic>\u2003=\u200375 samples, 150 concentrations) who received 6\u2010MP maintenance chemotherapy (titrated to a target dose of 75\u2003mg\u2003m<jats:sup>\u22122<\/jats:sup> day<jats:sup>\u22121<\/jats:sup>). All patients were genotyped for polymorphisms in three enzymes involved in 6\u2010MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (<jats:sc>nonmem<\/jats:sc>) to determine the population mean parameter estimate of clearance for the active metabolites.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The developed model revealed considerable interindividual variability (IIV) in the clearance of 6\u2010MP active metabolites [6\u2010thioguanine nucleotides (6\u2010TGNs) and 6\u2010methylmercaptopurine nucleotides (6\u2010mMPNs)]. Body surface area explained a significant part of 6\u2010TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (<jats:italic>P<\/jats:italic>\u2003&lt;\u20030.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6\u2010MP into 6\u2010TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6\u2010MP than the traditional empirical method since it combines the current practice of using body surface area in 6\u2010MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2008.03281.x","type":"journal-article","created":{"date-parts":[[2008,8,15]],"date-time":"2008-08-15T09:54:11Z","timestamp":1218794051000},"page":"826-837","source":"Crossref","is-referenced-by-count":43,"title":["Population pharmacokinetic and pharmacogenetic analysis of 6\u2010mercaptopurine in paediatric patients with acute lymphoblastic leukaemia"],"prefix":"10.1111","volume":"66","author":[{"given":"Ahmed 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