Re: Coding problem

Date: Sat, 05 Feb 2000 18:42:42 +1300 From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: Coding problem At first sight there seems to be some misthink going on here. AUC as I understand the term is the integral of conc over some time interval so that AUC(t) does not make sense unless the integration interval is specified AND the value of t for AUC(t) refers to some specific time related to the integration interval e.g. the mid-point. It is commonly believed in oncology that AUC has some special property for predicting drug effects but in fact it is just an empirical statistic that has some correlation with intensity of drug effect. If you insist on using AUC then you *can* use AUC(t) in an indirect effect model e.g. dadt(1) = -CL*A(1) ; solution is amount(t) in cpt 1 dadt(2) = A(1)/V ; solution is AUC(t) dadt(3) = Kin*(1-A(2)/(A(2)+IC50)) - Kout*A(3) ; soln is effect(t) Note that this model can only predict inceasing AUC(t) so that effect(t) will change monotonically and the effect of the drug cannot "wear off". Each successive dose will lead to a further increase of drug effect. If you arrange to "reset" the solution in compartment 2 after every dose (or dose cycle) (using EVID=4) then it is possible to relate the AUC(t) after each dose to the effect observed after that dose. However, overall I suggest it is makes more sense to use concentration(t) rather than AUC(t) to affect the indirect effect model because this will naturally take care of the onset and wearing off of effect after each dose. If you are smart enough to understand about indirect effect models which can describe the time course of response of biological mechanisms then I suggest you try hard to throw away the AUC concept and think more about biology when devising models for the time course of drug effect. Remember that the basic property of AUC is in some sense to discard time by integrating it away so it is not likely to be a helpful quantity to understand time related phenomena. -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556 http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm