{"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":1793255953512,"version":"4.5.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2013,3,15]],"date-time":"2013-03-15T00:00:00Z","timestamp":1363305600000},"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":[[2013,4]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>To determine the effect of increasing adult age on predicted metabolic drug clearance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Predicted metabolic drug clearances (<jats:styled-content style=\"fixed-case\">CL<jats:sub>PT<\/jats:sub><\/jats:styled-content>) were determined using<jats:italic>in vitro\u2010in vivo<\/jats:italic>extrapolation coupled with physiological\u2010based pharmacokinetic modelling and simulation (<jats:styled-content style=\"fixed-case\">IVIVE\u2010PBPK<\/jats:styled-content>) in Simcyp\u00ae. Simulations were conducted using<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>\u2010selective \u2018probe\u2019 drugs with subjects in 5 year age groups (20\u201325 to 90\u201395 years).<jats:styled-content style=\"fixed-case\">CL<jats:sub>PT<\/jats:sub><\/jats:styled-content>values were compared with human pharmacokinetic data stratified according to age (young = 20\u201340 years and elderly = 65\u201385 years) and gender. Age\u2010related changes in the physiological parameters used for<jats:styled-content style=\"fixed-case\">IVIVE<\/jats:styled-content>of<jats:styled-content style=\"fixed-case\">CL<jats:sub>PT<\/jats:sub><\/jats:styled-content>were described.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Predicted metabolic drug clearances decreased with increasing adult age to approximately 65\u201370 years: caffeine from 1.5 to 1.0\u2009ml\u2009min<jats:sup>\u22121<\/jats:sup>\u2009kg<jats:sup>\u22121<\/jats:sup>(a 33% decrease),<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>\u2010warfarin from 0.100 to 0.064\u2009ml\u2009min<jats:sup>\u22121<\/jats:sup>\u2009kg<jats:sup>\u22121<\/jats:sup>(36%),<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>\u2010mephenytoin from 4.1 to 2.5\u2009ml\u2009min<jats:sup>\u22121<\/jats:sup>\u2009kg<jats:sup>\u22121<\/jats:sup>(39%), desipramine from 10.6 to 7.3\u2009ml\u2009min<jats:sup>\u22121<\/jats:sup>\u2009kg<jats:sup>\u22121<\/jats:sup>(31%) and midazolam from 5.4 to 3.9\u2009ml\u2009min<jats:sup>\u22121<\/jats:sup>\u2009kg<jats:sup>\u22121<\/jats:sup>(27%). Except for<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>\u2010mephenytoin, predictions were within 3.5\u2010fold of clearances from clinical studies when stratified by age and gender. A trend towards higher<jats:styled-content style=\"fixed-case\">CL<jats:sub>PT<\/jats:sub><\/jats:styled-content>was observed in females, but this was only statistically significant in larger virtual trials. Physiological parameters that determine<jats:styled-content style=\"fixed-case\">CL<jats:sub>PT<\/jats:sub><\/jats:styled-content>decreased with increasing adult age: mean microsomal protein\u2009g<jats:sup>\u20131<\/jats:sup>of liver, liver weight, hepatic blood flow and human serum albumin concentration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Decreased metabolic clearance in the elderly was predicted by<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>imcyp\u00ae and was generally consistent with limited clinical data for four out of five drugs studied and the broader literature for drugs metabolized by<jats:styled-content style=\"fixed-case\">CYP<\/jats:styled-content>enzymes.<jats:styled-content style=\"fixed-case\">IVIVE\u2010PBPK<\/jats:styled-content>may be increasingly useful in predicting metabolic drug clearance in the 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