Re: metabolite modeling

Date: Mon, 13 Dec 1999 07:48:24 -0500 From: Nick Holford <n.holford@auckland.ac.nz> Subject: Re: metabolite modeling Leon, You make a good point that the fit may not be good when for parent and metabolite models. But this should be a cause for celebration not dismay. Anybody can fit the data separately and get what seem to be good fits but the good fits are not really any good if the parent and metabolite simultaneous fits are lousy. If the model does not fit the data then this is an opportunity to think more carefully about why the model is wrong (as you describe below) and learn more by searching for a better model. A simultaneous fit is an excellent method for evaluating the overlall parent and metabolite model. Because the a priori mechanistic link between parent and metabolite is so strong we should not be satisfied until a combined model is available or failing that a critical experiment is proposed to provide more data to understand the system better. -- Nick Holford, Center for Drug Development Science Georgetown University, 3900 Reservoir Rd NW, DC 20007-2197 email:n.holford@auckland.ac.nz tel:(202)687-1618 fax:687-0193 http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com> Subject: RE: metabolite modeling Date: Wed, 15 Dec 1999 14:00:36 +0100 The problem of precursor-product model identifiability has a long history. BTW, Professor Cobelli who invites us to Chicago 2000 contributed a lot to it in the 70th. The model that has just been discussed is a simplest one: the metabolite of interest is formed only systemically (i.e., no "first-pass" metabolism). Consider the situation when only plasma concentrations are available (no urine data that help identifying the model, as David Bourne mentioned). The identifiability problem can be solved (at least in case of a single individual) pretty well by assuming V(metabolite)=V(parent). However, if the metabolite is formed during absorption AND systemically (and this is rather a rule than an exception), the model remains unidentifiable unless we administer the metabolite to the same individual (if I recall it well this issue has been addressed in the paper by Venot et al. JPB 15:179-89, 1987). However, if we look at the problem from the population perspective it becomes almost inresolvable. And I ask myself: why do we need a full model? If the goal is to obtain a good approximation for the parent drug and the metabolite plasma concentration profiles that can be used for predictions (say for further PK-PD modelling) why not to fit independent models to the parent drug curve and the metabolite curve? In the latter case the "absorption" part can be modelled by a first- or zero-order process or by some combination. Of course this will make our model very empirical, however, as the matter of fact, all standard PK models are purely empirical, aren't they? Vladimir ---------------------------------------------------------------------- Vladimir Piotrovsky, Ph.D. Janssen Research Foundation Clinical Pharmacokinetics (ext. 5463) B-2340 Beerse Belgium Email: vpiotrov@janbe.jnj.com