{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T17:26:27Z","timestamp":1760549187316},"reference-count":56,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,8,6]],"date-time":"2012-08-06T00:00:00Z","timestamp":1344211200000},"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":[[2012,9]]},"abstract":"<jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003No consensus has been reached so far on the suitability of different methodologies for dose selection in children.<\/jats:p><jats:p>\u2022\u2003In paediatric drug development, initial estimation of the paediatric dose is obtained by extrapolation. This is usually performed using the dosing regimen in another population as reference. This approach also implies the possibility of using interpolations across age groups.<\/jats:p><jats:p>\u2022\u2003Midazolam, the paradigm compound selected for the purposes of our investigation, is a short\u2010acting imidazobenzodiazepine used for inducing sedation before medical procedures.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003The results of this analysis show that the use of allometric models to interpolate pharmacokinetics between paediatric subpopulations has limitations and drawbacks.<\/jats:p><jats:p>\u2022\u2003Estimation of covariate effects is critical, but not sufficient to interpolate parameter distributions and drug exposures from a reference population to another population.<\/jats:p><jats:p>\u2022\u2003The covariate\u2013parameter relationship does not remain constant beyond the range of observations. Exponential relationships used by allometry do not correct for these discrepancies.<\/jats:p><jats:p><jats:bold>AIM<\/jats:bold> The objective of this investigation was to assess the performance of an allometric model as the basis for interpolating drug exposure in the context of pharmacokinetic bridging across paediatric subpopulations.<\/jats:p><jats:p><jats:bold>METHODS<\/jats:bold> Midazolam was selected as a paradigm compound. Two nonlinear mixed effects models were developed to describe midazolam pharmacokinetics in infants, toddlers and adults (model 1) and in children and adolescents (model 2). Subsequently, systemic drug exposure, expressed in terms of the area under the concentration <jats:italic>vs<\/jats:italic>. time curve (AUC), in children and adolescents was interpolated based on pharmacokinetic parameter distributions obtained from the model describing infants, toddlers and adults (model 1). Results were compared with the values obtained from modelling of the data in the corresponding population (model 2).<\/jats:p><jats:p><jats:bold>RESULTS<\/jats:bold> The two pharmacokinetic models accurately described midazolam exposure in the population on which they were built. However, the model based on data from infants, toddlers and adults failed to predict the exposure observed in children and adolescents: the mean difference between the predicted and estimated AUC<jats:sub>0\u2013180<\/jats:sub> was of \u221217.8%, with a range of \u22126.8 to \u221238.4%.The discrepancy between estimated and interpolated exposure increased proportionally with body weight.<\/jats:p><jats:p><jats:bold>CONCLUSIONS<\/jats:bold> The current results indicate that irrespective of whether extrapolation or interpolation methods are to be applied during paediatric drug development, model predictions beyond the range of the data used for parameter estimation may be biased. For accurate inter\u2010 or extrapolation to different populations, the assumption of identical parameter\u2013covariate correlations across age groups may not be taken for granted.<\/jats:p>","DOI":"10.1111\/j.1365-2125.2012.04206.x","type":"journal-article","created":{"date-parts":[[2012,2,2]],"date-time":"2012-02-02T14:57:20Z","timestamp":1328194640000},"page":"525-535","source":"Crossref","is-referenced-by-count":21,"title":["Scaling of pharmacokinetics across paediatric populations: the lack of interpolative power of allometric models"],"prefix":"10.1111","volume":"74","author":[{"given":"Massimo","family":"Cella","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherijne","family":"Knibbe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saskia N.","family":"de Wildt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joop","family":"Van Gerven","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meindert","family":"Danhof","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oscar","family":"Della Pasqua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,8,6]]},"reference":[{"key":"e_1_2_6_2_2","unstructured":"FDAAA.Title IV: pediatric research equity act of 2007 (PREA) and Title V: best pharmaceuticals for children act of 2007 (BPCA). Public Law No. 110\u201085."},{"key":"e_1_2_6_3_2","unstructured":"European Parliament and Council of the European Union. Regulation (EC) No. 1901\/2006 on medicinal products for paediatric use."},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2009.03591.x"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.2131\/jts.34.SP307"},{"key":"e_1_2_6_6_2","unstructured":"European Medicines Agency.ICH Topic E11: clinical investigation of medicinal products in the paediatric population. CPMP\/ICH\/2711\/99.2001."},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.292"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2006.02622.x"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2008.03.016"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9592.2010.03473.x"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199630050-00001"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.48.113006.094708"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2011.539201"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.9.3658-3662.2005"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.234"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2005.02429.x"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01059477"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1109\/5.993400"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-198428060-00002"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-198503000-00017"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-0520"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1988.tb03127.x"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199812000-00020"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2004.09.004"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1754.1997.tb01611.x"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199902000-00020"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1994.186"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.2165\/11319970-000000000-00000"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200308000-00008"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200612000-00013"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200645090-00005"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/89.3.428"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1177\/00912700122012832"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1997.t01-1-00612.x"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.1997.t01-1-00613.x"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/jpepsy\/17.1.95"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aei104"},{"key":"e_1_2_6_38_2","first-page":"104","article-title":"Does age alter the pharmacokinetics of midazolam and 1\u2010OH\u2010midazolam in paediatric patients?","volume":"67","author":"De Wildt SN","year":"2000","journal-title":"Clin Pharmacol Ther"},{"key":"e_1_2_6_39_2","volume-title":"NONMEM 6,Ed. GloboMax, IDS","author":"Boeckman A","year":"2007"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-007-9361-x"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmpb.2007.12.002"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-006-9067-5"},{"key":"e_1_2_6_43_2","unstructured":"R Development Core Team.R: A language and environment for statistical computing. ed. R Foundation for statistical computing R Foundation for statistical computing Vienna Austria. ISBN 3\u2010900051\u201007\u20100 2010. Available athttp:\/\/www.R-project.org(last accessed 1 March 2012)."},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022972420004"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-007-0264-x"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.ccm.0000084806.15352.da"},{"key":"e_1_2_6_47_2","first-page":"86","volume-title":"Interspecies Pharmacokinetic Scaling: Principles and Application of Allometric Scaling","author":"Mahmood I","year":"1985"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2009.03484.x"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.csda.2008.08.021"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-010-0333-1"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470087978.ch39"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2011.03992.x"},{"key":"e_1_2_6_53_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.40.1.67"},{"key":"e_1_2_6_54_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-011-0369-x"},{"key":"e_1_2_6_55_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmps.1999.1284"},{"key":"e_1_2_6_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-007-9077-x"},{"key":"e_1_2_6_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1930"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1365-2125.2012.04206.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1365-2125.2012.04206.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T14:07:04Z","timestamp":1695478024000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/j.1365-2125.2012.04206.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8,6]]},"references-count":56,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,9]]}},"alternative-id":["10.1111\/j.1365-2125.2012.04206.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1365-2125.2012.04206.x","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,8,6]]}}}