ABSTRACT
Atypicalpopulationpharmacokineticdatasetconsistsofmeasureddrug concentrationswithassociatedsamplingtimesandknowndosehistories alongwithpatientcharacteristics(covariates)suchasage,weight,and gender.Atypicalpopulationpharmacodynamicdatasetconsistsofmeasuredresponses,dosehistories,andcovariates.Modelsforsuchdata attempttoidentifysourcesofvariabilityintheobserveddataandare increasinglybeingseenasanimportantaidindrugdevelopment.Inparticular,theidentificationofsubgroupsofpatients(forexample,theelderly) whoexhibitalteredbehaviorisimportantfortheselectionofoptimal doses.Inthischapterwestresstheimportanceofpredictivedistributions forconcentrations/responses.Suchdistributionscanbeusedfordoseselectionandformodelvalidationbothwithinandbetweenstudies.Here weconsiderdatafromfourphaseIstudiescollectedafteradministration ofthedrugrecombinanthirudin.Weusethedatafromtwoofthesestudies toconstructthepopulationmodelandthenvalidatethemodelusingthe datafromtheremainingtwostudies.Thestudieswereusedtoinvestigate theabsorptioncharacteristicsofthedrugandtheeffectofage,repeated
dosing,andsteady-statedosingonthepharmacokinetic/pharmacodynamicrelationship.
