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

Nick, James and all, I would like to add to the present discussion that when one estimates CL/fm or V/fm of the metabolite, one should be aware that if the parent drug is given orally (bioavailability unknown) this also affects the metabolite parameters. In this case only CL/(fm*F) and V/(fm*F) can be estimated. As has been already stated, this is not a problem for a descriptive model. However, especially for simulations it is important to account for the correlation of these parameters because CL/F and V/F of the parent as well as CL/(fm*F) and V/(fm*F) of the metabolite are all correlated because of F and fm. Thus my questions to the group: are the between subject variabilities of fm and F identifiable? I know that one can estimate them by fixing F and fm to 1 and estimate their omegas, but will they really be identifiable and give meaningful results? I'm wondering because also the parent drug's clearance and the fraction metabolised are related. Shouldn't this also be taken into account? Things get even more complicated when a significant first-past effect occurs. Then (assuming 100% absorption) the remainder of the unknown F, i.e. the fraction of the parent drug that is converted to the metabolite via first-pass (1-F) must now also be considered for the metabolite parameters and one estimates CL/(fm*F*(1-F)) and V/(fm*F*(1-F)). Or is F (assuming complete absorption) identifiable in this case? I'm looking forward to your comments. Regards, Andreas. ____________________________ Andreas Lindauer Department of Clinical Pharmacy Institute of Pharmacy University of Bonn An der Immenburg 4 D-53121 Bonn phone: + 49 228 73 5781 fax: + 49 228 73 9757