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
Simultaneous vs sequential for modeling parent AND metabolites in pop PK
Hello Alan
I have used a sequential approach in the past as the model was more
stable with lesser run time.
Atul
Venkatesh Atul Bhattaram
Pharmacometrics
Office of Clinical Pharmacology
US Food and Drug Administration
"The contents of this message are mine personally and do not necessarily
reflect any position of the Government or the Food and Drug
Administration."
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Xiao, Alan
Sent: Tuesday, December 09, 2008 11:02 AM
To: [email protected]
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
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.
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Xiao, Alan
Sent: Tuesday, December 09, 2008 11:02 AM
To: [email protected]
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
Hi Atul,
The emails must have crossed. However, this is not the FDA view based
on a recent experience where I have to repeat the analysis using the
simultaneous approach.
Kind regards,
Ziad
Dr Ziad Hussein
Senior Director, Pharmacometrics
ICON Development Solutions
Manchester
United Kingdom
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Bhattaram, Atul
Sent: 09 December 2008 16:22
To: Xiao, Alan; [email protected]
Subject: RE: [NMusers] Simultaneous vs sequential for modeling parent
AND metabolites in pop PK
Hello Alan
I have used a sequential approach in the past as the model was more
stable with lesser run time.
Atul
Venkatesh Atul Bhattaram
Pharmacometrics
Office of Clinical Pharmacology
US Food and Drug Administration
"The contents of this message are mine personally and do not necessarily
reflect any position of the Government or the Food and Drug
Administration."
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Xiao, Alan
Sent: Tuesday, December 09, 2008 11:02 AM
To: [email protected]
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
Hi Alan,
Like Bill mentioned above, the reason why the simultaneous approach rasises
questions is that the PK fitted with the simultaneous method can be quite
sensitive to PD model misspecification.
The publicatiosn below discussed the robusteness and performance of several
secinarios within the two methods (simultaneous vs. sequential):
1: Zhang L, Beal SL, Sheinerz LB. Simultaneous vs. sequential analysis
for population PK/PD data II: robustness of methods. J Pharmacokinet
Pharmacodyn. 2003 Dec;30(6):405-16.
2: Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis
for population PK/PD data I: best-case performance. J Pharmacokinet
Pharmacodyn. 2003 Dec;30(6):387-404.
*Murad Melhem, PhD*
*assistant Director Pk/PD*
*Cognigen Corp.*
*Buffalo, NY*
**
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
>
The appropriate approach is to fit parent compound and the metabolites
simultaneously, since it can help uniquely define the PK parameters,
especially the CL. As we know that CL is a lumped parameter without
metabolite information. Sequential estimation is the approach when there
is no better way to solve the problem in simultaneous fitting due to
numerical problem.
This is different situation from PK-PD fitting. In the situation if PD
has impact on PK, also, simultaneous fitting is the way to go.
xiaofeng
Xiaofeng Wang, PhD
Oncology, Novartis
(862)778-8856 (o)
"Xiao, Alan" <[EMAIL PROTECTED]>
Sent by: [EMAIL PROTECTED]
12/09/2008 01:30 PM
To
"Bachman, William" <[EMAIL PROTECTED]>, <[email protected]>
cc
Subject
RE: [NMusers] Simultaneous vs sequential for modeling parent AND
metabolites in pop PK
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
Quoted reply history
-----Original Message-----
From: Bachman, William [mailto:[EMAIL PROTECTED]
Sent: Tuesday, December 09, 2008 11:26 AM
To: Xiao, Alan
Cc: [email protected]
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: [email protected]
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
Hi,
Experimental studies (rather than just opinion) can be found here:
1. Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. J Pharmacokinet Pharmacodyn. 2003;30(6):387-404. 2. Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis for population PK/PD data II: robustness of methods. J Pharmacokinet Pharmacodyn. 2003;30(6):405-16. 3. Proost JH, Schiere S, Eleveld DJ, Wierda JM. Simultaneous versus sequential pharmacokinetic-pharmacodynamic population analysis using an iterative two-stage Bayesian technique. Biopharm Drug Dispos. 2007;28(8):455-73.
My interpretation of these studies is that one should use a sequential approach to build the model then try a simultaneous fit. If the PK part of the model changes 'importantly' (subjective decision) with the simultaneous fit then this can be a clue to model misspecification in the link between the PK and PD parts of the model (see second paper by Zhang et al).
Nick
Hussein, Ziad wrote:
> Hi Alan,
>
> I just had a very recent experience few weeks ago for a sequential PopPK
> for parent and metabolite that was submitted to the FDA and they came
> back and asked for simultaneous modelling.
>
> Whether this is scientific or not the FDA view should be taken into
> consideration.
>
> Kind regards,
> Ziad
>
Quoted reply history
> -----Original Message-----
> From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
> On Behalf Of Xiao, Alan
> Sent: 09 December 2008 16:02
> To: [email protected]
> 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
>
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
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Nick Holford
Sent: 09 December 2008 20:52
To: [email protected]
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: [email protected]
> 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: [email protected]
> 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
>
James,
All is well with me and it seems things continue to be (w)right for you :-)
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. 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.
Best wishes,
Nick
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
>
Quoted reply history
> -----Original Message-----
> From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
> On Behalf Of Nick Holford
> Sent: 09 December 2008 20:52
> To: [email protected]
> 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: [email protected]
> > 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: [email protected]
> > 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
> >
>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
>
>
Quoted reply history
> -----Original Message-----
> From: [EMAIL PROTECTED]
[mailto:[EMAIL PROTECTED]
> On Behalf Of Nick Holford
> Sent: 09 December 2008 20:52
> To: [email protected]
> 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: [email protected]
>> 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: [email protected]
>> 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
>>
Dear Dr. Holford,
All I was suggesting was that once you have decided on which assumption you
like the most and start modeling the metabolite data then shouldn't
simultaneous modeling of the parent + metabolite be more preferable? The model
will take long run time any ways because it will be a $DES model. By doing
simultaneous modeling of the parent + metabolite you will probably improve the
parameters of the parent drug because the metabolite information will bolster
the parameters of the parent drug. Similarly common parameters between the
parent and metabolite will benefit as well because of the simultaneous
estimation.
Of course if the metabolite data is really dirty and you are really afraid that
the metabolite data will contaminate the parent drug's parameters then that
situation seems to be a reasonable place to try sequential modeling.
Kindly advise,
Mahesh
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED]
[mailto:[EMAIL PROTECTED] Behalf Of Nick Holford
Sent: Wednesday, December 10, 2008 3:12 PM
To: [email protected]
Subject: Re: [NMusers] Simultaneous vs sequential for modeling parent
AND metabolites in pop PK
James, Mahesh,
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".
As I never said this was a fallacy I dont think you need be stressed by
it. Everytime you use a model to describe oral PK data alone you must
make an assumption about the dose that is absorbed. By default NONMEM
will make the assumption that Foral=1 but of course when you interpret
the parameters you should remember the assumption.
Similarly you may assume Fm=1 and estimate metabolite parameters of
CLm/Fm and Vm/Fm where Fm is the fraction of parent converted to
metabolite. For simply descriptive purposes the Fm=1 assumption is fine
but more might be learned by making a different assumption (as Mahesh
points out). Fm might be guessable from in vitro descriptions of
metabolism or one may assume a Vm (metabolite volume) perhaps the same
as the parent. The latter can aid in proposing plausible values for Fm
but the descriptive value of the model is unchanged whichever assumption
is used.
I dont understand why Mahesh adds to each of the assumptions "[and
preferably do simultaneous parent/metabolite modeling]". Perhaps he
could give some reasons for this because I dont see it has anything to
do with the choice of which assumption to make.
IMHO the important thing is to recognize that an assumption must be
made. I have seen people use NONMEM to estimate Fm and CLm and Vm as if
they could identify these 3 parameters independently. NONMEM will do
what it is told and make estimates of the parameters even though one of
them cannot be identified. This is the important lesson to learn for
those who have not had experience of parent metabolite modelling with
NONMEM.
I want to stick to my original assertion that PKPD and parent-metabolite
models are similar when applying a modelling strategy of either
sequential or simultaneous fitting of data.
We should remember the Box aphorism "All models are wrong but some
models are useful". Part of the process is modelling is to evaluate the
model to see how wrong it is. The sequential then simultaneous approach
can be helpful for model evaluation as described by Liping Zhang in her
second paper on PKPD models.
I see no reason why this should not apply to parent-metabolite models.
However, usually parent-metabolite models are simpler because commonly
one has first-order kinetics and essentially immediate conversion of
parent to metabolite. The implicit assumptions of complete, rapid and
first-order conversion may be fine but it still sensible to look at the
data to check that these assumptions are compatible with the results
from a sequential model.
Nick
James G Wright wrote:
>> 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
>
>
Mahesh wrote:
> Dear NMusers,
> I think in trying to generalize the case between sequential PK/PD vs.
> sequential parent/metabolite we maybe forgetting some PK concepts.
>
> 1) In the case of parent/metabolite modeling the metabolite data often
> carries important information about the parent drug.
> Eg.a. If there is formation limited kinetics going on then the
> terminal slopes of the parent and metabolite will both be reflective
> of the parent's kel
> Eg.b. If there is severe flip-flop kinetics going on then the
> terminal slopes of the parent and metabolite will both be reflective
> of the parent drug's ka
> 2) There are common parameters (e.g.. k-metabolite) between the parent
> and metabolite that may be estimated in a more meaningful manner using
> simultaneous modeling.
>
> Given these considerations, my guess is that simultaneous modeling of
> the parent and metabolite maybe more scientifically useful (use all
> the information to get the best parameter estimates).
>
> On a related note; it is generally well known that if you administer
> only the parent and measure parent & metabolite then the volume of
> metabolite is not identifiable. In this case there are 3 options:
> a) Fix the metabolite volume to that of the parent [and preferably do
> simultaneous parent/metabolite modeling]
> b) Use prior knowledge to assign a fixed fraction of the parent to
> get converted to metabolite [and preferably do simultaneous
> parent/metabolite modeling]
> c) If you have no idea about the Vm or fm then use a sequential
> empirical (transit/delay) compartmental modeling recently described by
> Don Mager in a DMD paper [2004 Aug;32(8):786-93]
>
> Is there any consensus on which of these 3 approaches to use.
>
> Best regards,
> Mahesh
--
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
Ziad:
When FDA sends out a request, there should be a rationale for it. If it
is not clear enough, the sponsors should ask for clarification. If after
clarification, the sponsors felt the rationale is not scientific, then
the sponsors should not hesitate to appeal such requests. The sponsors
can appeal to the Director of Pharmacometrics at FDA if necessary.
Yaning
Yaning Wang, Ph.D.
Team Leader, Pharmacometrics
Office of Clinical Pharmacology
Office of Translational Science
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Phone: 301-796-1624
Email: [EMAIL PROTECTED]
"The contents of this message are mine personally and do not necessarily
reflect any position of the Government or the Food and Drug
Administration."
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Hussein, Ziad
Sent: Tuesday, December 09, 2008 11:38 AM
To: Xiao, Alan; [email protected]
Subject: RE: [NMusers] Simultaneous vs sequential for modeling parent
AND metabolites in pop PK
Hi Alan,
I just had a very recent experience few weeks ago for a sequential PopPK
for parent and metabolite that was submitted to the FDA and they came
back and asked for simultaneous modelling.
Whether this is scientific or not the FDA view should be taken into
consideration.
Kind regards,
Ziad
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Xiao, Alan
Sent: 09 December 2008 16:02
To: [email protected]
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
James,
I tried to deal with this in my previous reply. We do not differ. It is fine for me if you make the assumption that you do not know Fm and you estimate CLm/Fm and Vm/Fm. But this assumption in practice is an assumption that Fm=1 when you actually are estimating the parameters.
There are other assumptions that can be made depending on what you know.
Nick
James G Wright wrote:
> Hi Nick,
> You have written many things that are true, however I think we are
> differing on a very essential point.
>
> > Nick Holford wrote
>
> > Everytime you use a model to describe oral PK data alone you must make an assumption about the dose that is absorbed.
>
> You could make an assumption about this if you wanted to. Or you can be
> transparent and admit that you don't know F, and therefore are
> estimating apparent parameters e.g CL/F, V/F. Any assumption about F is
>
> extrinsic to the model - it is not required.
>
> This is equally true for modelling the metabolite where the fraction of
> the dose that becomes metabolite is unknown - we are estimating CL/F,
> V/F etc. for the metabolite. Any assumption about F, V etc. is again
> optional.
>
> Do you agree?
>
> Best regards, James
>
> James G Wright PhD
> Scientist
> Wright Dose Ltd
> Tel: 44 (0) 772 5636914
>
Quoted reply history
> -----Original Message-----
> From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
> On Behalf Of Samtani, Mahesh [PRDUS]
> Sent: 10 December 2008 21:18
> To: Nick Holford; [email protected]
> Subject: RE: [NMusers] Simultaneous vs sequential for modeling parent
> AND metabolites in pop PK
>
> Dear Dr. Holford,
> All I was suggesting was that once you have decided on which assumption
> you like the most and start modeling the metabolite data then shouldn't
> simultaneous modeling of the parent + metabolite be more preferable? The
> model will take long run time any ways because it will be a $DES model.
> By doing simultaneous modeling of the parent + metabolite you will
> probably improve the parameters of the parent drug because the
> metabolite information will bolster the parameters of the parent drug.
> Similarly common parameters between the parent and metabolite will
> benefit as well because of the simultaneous estimation.
>
> Of course if the metabolite data is really dirty and you are really
> afraid that the metabolite data will contaminate the parent drug's
> parameters then that situation seems to be a reasonable place to try
> sequential modeling.
>
> Kindly advise,
> Mahesh
>
> -----Original Message-----
> From: [EMAIL PROTECTED]
> [mailto:[EMAIL PROTECTED] Behalf Of Nick Holford
> Sent: Wednesday, December 10, 2008 3:12 PM
> To: [email protected]
> Subject: Re: [NMusers] Simultaneous vs sequential for modeling parent
> AND metabolites in pop PK
>
> James, Mahesh,
>
> 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".
>
> As I never said this was a fallacy I dont think you need be stressed by it. Everytime you use a model to describe oral PK data alone you must make an assumption about the dose that is absorbed. By default NONMEM will make the assumption that Foral=1 but of course when you interpret the parameters you should remember the assumption.
>
> Similarly you may assume Fm=1 and estimate metabolite parameters of CLm/Fm and Vm/Fm where Fm is the fraction of parent converted to metabolite. For simply descriptive purposes the Fm=1 assumption is fine but more might be learned by making a different assumption (as Mahesh points out). Fm might be guessable from in vitro descriptions of metabolism or one may assume a Vm (metabolite volume) perhaps the same as the parent. The latter can aid in proposing plausible values for Fm but the descriptive value of the model is unchanged whichever assumption
>
> is used.
>
> I dont understand why Mahesh adds to each of the assumptions "[and preferably do simultaneous parent/metabolite modeling]". Perhaps he could give some reasons for this because I dont see it has anything to do with the choice of which assumption to make.
>
> IMHO the important thing is to recognize that an assumption must be made. I have seen people use NONMEM to estimate Fm and CLm and Vm as if they could identify these 3 parameters independently. NONMEM will do what it is told and make estimates of the parameters even though one of them cannot be identified. This is the important lesson to learn for those who have not had experience of parent metabolite modelling with NONMEM.
>
> I want to stick to my original assertion that PKPD and parent-metabolite
>
> models are similar when applying a modelling strategy of either sequential or simultaneous fitting of data.
>
> We should remember the Box aphorism "All models are wrong but some models are useful". Part of the process is modelling is to evaluate the model to see how wrong it is. The sequential then simultaneous approach can be helpful for model evaluation as described by Liping Zhang in her second paper on PKPD models.
>
> I see no reason why this should not apply to parent-metabolite models. However, usually parent-metabolite models are simpler because commonly one has first-order kinetics and essentially immediate conversion of parent to metabolite. The implicit assumptions of complete, rapid and first-order conversion may be fine but it still sensible to look at the data to check that these assumptions are compatible with the results from a sequential model.
>
> Nick
>
> James G Wright wrote:
>
> > > 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
>
> Mahesh wrote:
>
> > Dear NMusers,
> >
> > I think in trying to generalize the case between sequential PK/PD vs. sequential parent/metabolite we maybe forgetting some PK concepts. 1) In the case of parent/metabolite modeling the metabolite data often
>
> > carries important information about the parent drug. Eg.a. If there is formation limited kinetics going on then the terminal slopes of the parent and metabolite will both be reflective of the parent's kel Eg.b. If there is severe flip-flop kinetics going on then the terminal slopes of the parent and metabolite will both be reflective of the parent drug's ka
> >
> > 2) There are common parameters (e.g.. k-metabolite) between the parent
>
> > and metabolite that may be estimated in a more meaningful manner using
>
> > simultaneous modeling.
> >
> > Given these considerations, my guess is that simultaneous modeling of the parent and metabolite maybe more scientifically useful (use all the information to get the best parameter estimates). On a related note; it is generally well known that if you administer only the parent and measure parent & metabolite then the volume of metabolite is not identifiable. In this case there are 3 options: a) Fix the metabolite volume to that of the parent [and preferably do simultaneous parent/metabolite modeling] b) Use prior knowledge to assign a fixed fraction of the parent to get converted to metabolite [and preferably do simultaneous parent/metabolite modeling] c) If you have no idea about the Vm or fm then use a sequential empirical (transit/delay) compartmental modeling recently described by
>
> > Don Mager in a DMD paper [2004 Aug;32(8):786-93]
> >
> > Is there any consensus on which of these 3 approaches to use. Best regards,
> >
> > Mahesh
--
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
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
Nick,
My apologies for labouring the point. I had read your reply as implying
that an assumption about F (or V) was a necessary part of the model.
With metabolite models, this perception is widespread (and often
repeated, sometimes even on nmusers) and I just wanted to be absolutely
clear on which assumptions are necessary and which are optional.
I am pleased we are in agreement that assumptions about F= are entirely
optional.
Best regards, James
James G Wright PhD
Scientist
Wright Dose Ltd
Tel: 44 (0) 772 5636914
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Nick Holford
Sent: 11 December 2008 00:35
To: [email protected]
Subject: [!! SPAM] Re: [NMusers] Simultaneous vs sequential for modeling
parent AND metabolites in pop PK
James,
I tried to deal with this in my previous reply. We do not differ. It is
fine for me if you make the assumption that you do not know Fm and you
estimate CLm/Fm and Vm/Fm. But this assumption in practice is an
assumption that Fm=1 when you actually are estimating the parameters.
There are other assumptions that can be made depending on what you know.
Nick
James G Wright wrote:
> Hi Nick,
> You have written many things that are true, however I think we are
> differing on a very essential point.
>
>
>> Nick Holford wrote
>>
>
>
>> Everytime you use a model to describe oral PK data alone you must
>> make an assumption about the dose that is absorbed.
>>
>
> You could make an assumption about this if you wanted to. Or you can
be
> transparent and admit that you don't know F, and therefore are
> estimating apparent parameters e.g CL/F, V/F. Any assumption about F
is
> extrinsic to the model - it is not required.
>
> This is equally true for modelling the metabolite where the fraction
of
> the dose that becomes metabolite is unknown - we are estimating CL/F,
> V/F etc. for the metabolite. Any assumption about F, V etc. is again
> optional.
>
> Do you agree?
>
> Best regards, James
>
> James G Wright PhD
> Scientist
> Wright Dose Ltd
> Tel: 44 (0) 772 5636914
>
>
> -----Original Message-----
> From: [EMAIL PROTECTED]
[mailto:[EMAIL PROTECTED]
> On Behalf Of Samtani, Mahesh [PRDUS]
> Sent: 10 December 2008 21:18
> To: Nick Holford; [email protected]
> Subject: RE: [NMusers] Simultaneous vs sequential for modeling parent
> AND metabolites in pop PK
>
> Dear Dr. Holford,
> All I was suggesting was that once you have decided on which
assumption
> you like the most and start modeling the metabolite data then
shouldn't
> simultaneous modeling of the parent + metabolite be more preferable?
The
> model will take long run time any ways because it will be a $DES
model.
> By doing simultaneous modeling of the parent + metabolite you will
> probably improve the parameters of the parent drug because the
> metabolite information will bolster the parameters of the parent drug.
> Similarly common parameters between the parent and metabolite will
> benefit as well because of the simultaneous estimation.
>
> Of course if the metabolite data is really dirty and you are really
> afraid that the metabolite data will contaminate the parent drug's
> parameters then that situation seems to be a reasonable place to try
> sequential modeling.
>
> Kindly advise,
> Mahesh
>
> -----Original Message-----
> From: [EMAIL PROTECTED]
> [mailto:[EMAIL PROTECTED] Behalf Of Nick Holford
> Sent: Wednesday, December 10, 2008 3:12 PM
> To: [email protected]
> Subject: Re: [NMusers] Simultaneous vs sequential for modeling parent
> AND metabolites in pop PK
>
>
> James, Mahesh,
>
> 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".
>
> As I never said this was a fallacy I dont think you need be stressed
by
> it. Everytime you use a model to describe oral PK data alone you must
> make an assumption about the dose that is absorbed. By default NONMEM
> will make the assumption that Foral=1 but of course when you
interpret
> the parameters you should remember the assumption.
>
> Similarly you may assume Fm=1 and estimate metabolite parameters of
> CLm/Fm and Vm/Fm where Fm is the fraction of parent converted to
> metabolite. For simply descriptive purposes the Fm=1 assumption is
fine
> but more might be learned by making a different assumption (as Mahesh
> points out). Fm might be guessable from in vitro descriptions of
> metabolism or one may assume a Vm (metabolite volume) perhaps the same
> as the parent. The latter can aid in proposing plausible values for Fm
> but the descriptive value of the model is unchanged whichever
assumption
>
> is used.
>
> I dont understand why Mahesh adds to each of the assumptions "[and
> preferably do simultaneous parent/metabolite modeling]". Perhaps he
> could give some reasons for this because I dont see it has anything to
> do with the choice of which assumption to make.
>
> IMHO the important thing is to recognize that an assumption must be
> made. I have seen people use NONMEM to estimate Fm and CLm and Vm as
if
> they could identify these 3 parameters independently. NONMEM will do
> what it is told and make estimates of the parameters even though one
of
> them cannot be identified. This is the important lesson to learn for
> those who have not had experience of parent metabolite modelling with
> NONMEM.
>
> I want to stick to my original assertion that PKPD and
parent-metabolite
>
> models are similar when applying a modelling strategy of either
> sequential or simultaneous fitting of data.
>
> We should remember the Box aphorism "All models are wrong but some
> models are useful". Part of the process is modelling is to evaluate
the
> model to see how wrong it is. The sequential then simultaneous
approach
> can be helpful for model evaluation as described by Liping Zhang in
her
> second paper on PKPD models.
>
> I see no reason why this should not apply to parent-metabolite models.
> However, usually parent-metabolite models are simpler because commonly
> one has first-order kinetics and essentially immediate conversion of
> parent to metabolite. The implicit assumptions of complete, rapid and
> first-order conversion may be fine but it still sensible to look at
the
> data to check that these assumptions are compatible with the results
> from a sequential model.
>
> Nick
>
> James G Wright wrote:
>
>>> 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
>>
>>
>>
> Mahesh wrote:
>
>
>> Dear NMusers,
>> I think in trying to generalize the case between sequential PK/PD vs.
>> sequential parent/metabolite we maybe forgetting some PK concepts.
>>
>> 1) In the case of parent/metabolite modeling the metabolite data
often
>>
>
>
>> carries important information about the parent drug.
>> Eg.a. If there is formation limited kinetics going on then the
>> terminal slopes of the parent and metabolite will both be reflective
>> of the parent's kel
>> Eg.b. If there is severe flip-flop kinetics going on then the
>> terminal slopes of the parent and metabolite will both be reflective
>> of the parent drug's ka
>> 2) There are common parameters (e.g.. k-metabolite) between the
parent
>>
>
>
>> and metabolite that may be estimated in a more meaningful manner
using
>>
>
>
>> simultaneous modeling.
>>
>> Given these considerations, my guess is that simultaneous modeling of
>> the parent and metabolite maybe more scientifically useful (use all
>> the information to get the best parameter estimates).
>>
>> On a related note; it is generally well known that if you administer
>> only the parent and measure parent & metabolite then the volume of
>> metabolite is not identifiable. In this case there are 3 options:
>> a) Fix the metabolite volume to that of the parent [and preferably do
>> simultaneous parent/metabolite modeling]
>> b) Use prior knowledge to assign a fixed fraction of the parent to
>> get converted to metabolite [and preferably do simultaneous
>> parent/metabolite modeling]
>> c) If you have no idea about the Vm or fm then use a sequential
>> empirical (transit/delay) compartmental modeling recently described
by
>>
>
>
>> Don Mager in a DMD paper [2004 Aug;32(8):786-93]
>>
>> Is there any consensus on which of these 3 approaches to use.
>>
>> Best regards,
>> Mahesh
>>
>
>
--
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