RE: Simultaneous vs sequential for modeling parent AND metabolites in pop PK

>Nick Holford wrote: >Non-proportionality (aka non-linearity) of metabolite formation from >parent is not really an issue. With the right design (i.e. suitable >doses of parent) then this can be discovered from just giving the >parent. The key assumptions of metabolite models are about how the metabolite is formed - linearly or nonlinearly, from plasma or during first-pass, immediately or not. Making sure your assumptions are true is really the issue for me with any analysis. >But to really know how much of the parent is eventually >transformed to the metabolite needs additional information i.e. direct >administration of the metabolite. Of course, if fraction formed is the parameter that you need to estimate. Fitting a metabolite PK model is not dependent on assuming 100% metabolite formation from parent, as you originally stated, unless you mislabel the parameters as actual CL, instead of CL/F. Not knowing F doesn't affect the application and predictive utility of the model any more than not knowing F for the parent after oral administration. The widespread presentation of "F=1" as an "unverifiable assumption" causes model end-users to suspect that the assumption could in some sense be wrong ("Aah, but how do you know F=1?"), leading to the perception that the metabolite model is misleading and unreliable. I think it would be helpful if you could explicitly retract your assertion regarding the assumption "that all drug goes to metabolite". The "F=1 fallacy" has caused me no end of stress over the years, and next time I may have to contend with the (almost irrefutable) argument "but Nick Holford said it was true". Best regards, James James G Wright wrote: > Hi Nick, > > I hope all is well with you - good to see you are keeping the nmusers in > line :-). > > I am not sure I agree with your second paragraph as I have understood > it. When I fit a parent-metabolite model, I estimate CL/F and V/F for > the metabolite. Frequently, I hear the widespread misconception that I > have assumed all of the parent goes to metabolite, but this would only > be true if I claimed to have estimated CL, rather than CL/F. This is > exactly the same as if I analyse the parent after oral administration > (without IV) - we don't assume all the drug is absorbed, we simply > estimated the ratio of CL and V to F. > > The real assumption lies in the form of the link between parent and > metabolite - for example, that it is linearly formed from parent in > plasma. It is this assumption that may need to be more rigorously > evaluated, and exactly the point highlighted in your first paragraph. > For example, there can be an apparent delay in metabolite formation > relative to parent plasma concentrations and/or the metabolite may be > formed during the first-pass. > > Best regards, James > > PS One can get technical and claim there needs to be a correction for > molecular weight in F for the metabolite, but the importance of this > depends on how the parameter will actually be used. > > James G Wright PhD > Scientist > Wright Dose Ltd > Tel: 44 (0) 772 5636914 > >