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 -----Original Message----- From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of Nick Holford Sent: 09 December 2008 20:52 To: nmusers@globomaxnm.com Subject: Re: [NMusers] Simultaneous vs sequential for modeling parent AND metabolites in pop PK Alan, The comments about sequential vs simultaneous modelling apply for any kind of multivariate approach. The 'driver' model e.g. parent conc for metabolite or the 'driven' model e.g. metabolite from parent will be dependent on having a good driver model first. If the driver plus driven dont do well together with a simultaneous fit then this is a clue to model misspecification. Parent-metabolite models nearly always have to make at least one unverifiable assumption if the metabolite is not given directly. (e.g. one may assume all of the parent goes to metabolite OR assume a volume for the metabolite). PKPD models also have unverifiable assumptions e.g. concentration at the site of the drug effect. Nick Xiao, Alan wrote: > Dear All, > > Thanks for your response and I'm sorry for the confusion. > > I'm talking about the sequential/simultaneous modeling to fit parent > concentrations AND metabolites in pop PK, not about PD data at all. > > That is for sequential approach, you develop a model to fit the parent data > first and then fix the PK parameters for parents to develop a model > to fit the metabolite. While, for simultaneous approach, you develop a model to > fit both parent and metabolites simultaneously > (to simultaneously estimate parameters for both parent and metabolites). > > Alan > > -----Original Message----- > From: Bachman, William [mailto:[EMAIL PROTECTED] > Sent: Tuesday, December 09, 2008 11:26 AM > To: Xiao, Alan > Cc: nmusers@globomaxnm.com > Subject: RE: [NMusers] Simultaneous vs sequential for modeling parent > AND metabolites in pop PK > > > The argument against the simultaneous approach is that the PD data can > "drive" the PK model, particulary since the PD data usually has more > variability. > > -----Original Message----- > From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] > On Behalf Of Xiao, Alan > Sent: Tuesday, December 09, 2008 11:02 AM > To: nmusers@globomaxnm.com > Subject: [NMusers] Simultaneous vs sequential for modeling parent AND > metabolites in pop PK > > Dear All, > > I know this is an old topic but would like to see the statistics. > > When you have to develop a pop PK model for both parent and active > metabolites, which approach do you prefer or have you used most: > simultaneous or sequential? Which way do you think is more scientific? I > heard comments saying that the simultaneous approach is not scientific. > > Thanks, > > Alan > ICON plc made the following annotations. > ------------------------------------------------------------------------ ------ > This e-mail transmission may contain confidential or legally privileged information > that is intended only for the individual or entity named in the e-mail address. If you > are not the intended recipient, you are hereby notified that any disclosure, copying, > distribution, or reliance upon the contents of this e-mail is strictly prohibited. If > you have received this e-mail transmission in error, please reply to the sender, so that > ICON plc can arrange for proper delivery, and then please delete the message. > Thank You, > ICON plc > South County Business Park > Leopardstown > Dublin 18 > Ireland > Registered number: 145835 > > > -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand [EMAIL PROTECTED] tel:+64(9)923-6730 fax:+64(9)373-7090 http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
