Dear NMusers,
we have a question we have been debating in our group, we have come to an agreement, and we would like the input from the NMusers community. It is about how to report values for clearances and volumes when the relative bioavailability is fixed to values different from 1 in some of the subjects.
We developed a 2 compartment POPK model for an orally administered drug that is a substrate of polymorphic enzyme. Individuals are categorized as slow, intermediate and fast metabolizers.
Since no IV data were available, relative bioavailability was fixed to 1 for slow metabolizers, and it was found to be 20% lower (and thus 0.8) in fast and intermediate metabolizers. On top of this difference in bioavailability, clearance was estimated to be 6, 11 and 14 L/h for slow, intermediate and fast metabolizers, respectively. The other clearances and volumes in the model (V, Q, V3) were the same in the three groups.
Our question is on how to report clearances and volumes for each group of metabolizers.
Since we only have oral data, we can only estimate oral clearance (e.g. CL/F), and normally this is what we would like to report, but in our case this means dividing the values of CL provided by NONMEM for the different metabolizers by their respective bioavailability. This would imply reporting 3 different values not only for CL/F, but also for V/F, Q/F and V3/F, resulting in a over-populated table.
Moreover, since the model contains BSV both in CL and bioavailability, also the BSV of CL/F should be calculated if we want to report it.
For these reasons, we decided it is best to report the "pure" values of CL, V, Q and V3 used in the NONMEM model, and then state that, to obtain CL/F, V/F, Q/F and V3/F, one should divide by the respective bioavailability. Does this make sense?
If so, how would you indicate the parameters in the table? Calling it only CL gives the idea that we are providing the value of absolute CL, which is not possible without IV data. What we are indeed reporting are the values of CL (or V, Q, V3), if the bioavailability is fixed to a certain value (1 for slow metabolizers, and 0.8 for intermediate and fast). Is there a specific name that could be used for that? Would a simple explanation under the table be acceptable?
What is the experience of the community with this? Any suggestions?
Thank you in advance for your help,
The pharmacometrics group at the University of Cape Town
--
------------------------------------------------
Paolo Denti, PhD
Junior Lecturer
Division of Clinical Pharmacology
Department of Medicine
University of Cape Town
K45 Old Main Building
Groote Schuur Hospital
Observatory, Cape Town
7925 South Africa
phone: +27 21 404 7719
fax: +27 21 448 1989
email: [email protected]
The theory of relativity for CL and V...
Dear Paolo,
If I have understood your problem correctly, I have pondered this for a similar situation. I formatted the table so that each subpopulation was on a different row and then reported CL/Frel, using the rel subscript (short for relative) to place emphasis on the F differing among subpopulations. I also included Frel as the last column of the table, so it is explicitly visible in the table...Then I placed an explanation in the Table caption, the methods section, the results section and the discussion section so no-one missed it. My opinion at the time was that the only way to make the table smaller was to lose important information.
If peer reviewing, I probably wouldn't object to report the CL values etc. for F=1 (which you call pure) but I prefer to explicitly acknowledge the role of differing F's than leave it for the reader to calculate. For readers concerned about AUC as a function of drug dose, it is the actual CL/Frel that is the driver of drug exposure.
I would want to see the subpopulation relative F's somewhere in the parameter table for clarity.
Best regards, James
Quoted reply history
On 07/01/2013 13:19, Paolo Denti wrote:
> Dear NMusers,
>
> we have a question we have been debating in our group, we have come to an agreement, and we would like the input from the NMusers community. It is about how to report values for clearances and volumes when the relative bioavailability is fixed to values different from 1 in some of the subjects.
>
> We developed a 2 compartment POPK model for an orally administered drug that is a substrate of polymorphic enzyme. Individuals are categorized as slow, intermediate and fast metabolizers.
>
> Since no IV data were available, relative bioavailability was fixed to 1 for slow metabolizers, and it was found to be 20% lower (and thus 0.8) in fast and intermediate metabolizers. On top of this difference in bioavailability, clearance was estimated to be 6, 11 and 14 L/h for slow, intermediate and fast metabolizers, respectively. The other clearances and volumes in the model (V, Q, V3) were the same in the three groups.
>
> Our question is on how to report clearances and volumes for each group of metabolizers.
>
> Since we only have oral data, we can only estimate oral clearance (e.g. CL/F), and normally this is what we would like to report, but in our case this means dividing the values of CL provided by NONMEM for the different metabolizers by their respective bioavailability. This would imply reporting 3 different values not only for CL/F, but also for V/F, Q/F and V3/F, resulting in a over-populated table.
>
> Moreover, since the model contains BSV both in CL and bioavailability, also the BSV of CL/F should be calculated if we want to report it.
>
> For these reasons, we decided it is best to report the "pure" values of CL, V, Q and V3 used in the NONMEM model, and then state that, to obtain CL/F, V/F, Q/F and V3/F, one should divide by the respective bioavailability. Does this make sense?
>
> If so, how would you indicate the parameters in the table? Calling it only CL gives the idea that we are providing the value of absolute CL, which is not possible without IV data. What we are indeed reporting are the values of CL (or V, Q, V3), if the bioavailability is fixed to a certain value (1 for slow metabolizers, and 0.8 for intermediate and fast). Is there a specific name that could be used for that? Would a simple explanation under the table be acceptable?
>
> What is the experience of the community with this? Any suggestions?
>
> Thank you in advance for your help,
> The pharmacometrics group at the University of Cape Town
--
James G Wright PhD,
Scientist, Wright Dose Ltd
Tel: UK (0)772 5636914
Dear Paolo,
The reduced bioavailability is most likely a result of increased,
however variable, pre-systemic metabolism which also correlates with
systemic clearance. Have you tried linking these together in your model,
e.g. with a well-stirred liver model (e.g. Gordi et al Br J Clin
Pharmacol. 2005 Feb;59(2):189-98.)? This would most likely give you a
more accurate estimation of (relative) bioavailability, and thus
clearance and volume of distribution in comparison with a model with a
BSV on CL/F and a separate BSV on F.
Perhaps off-topic: What drug are you studying? Efavirenz? The
CYP2B6-mediated metabolite 8-hydroxyefavirenz may be easily measured.
You could investigate whether metabolite data support your hypothesis.
Cheers,
Rob
------
R. ter Heine, PhD, PharmD
Hospital pharmacist i.t.
Meander Medical Center, Amersfoort, The Netherlands
T: +31-33-8502335
E: [email protected]
-----Oorspronkelijk bericht-----
Quoted reply history
Van: [email protected] [mailto:[email protected]]
Namens Paolo Denti
Verzonden: maandag 7 januari 2013 14:19
Aan: NMusers
Onderwerp: [NMusers] The theory of relativity for CL and V...
Dear NMusers,
we have a question we have been debating in our group, we have come to
an agreement, and we would like the input from the NMusers community. It
is about how to report values for clearances and volumes when the
relative bioavailability is fixed to values different from 1 in some of
the subjects.
We developed a 2 compartment POPK model for an orally administered drug
that is a substrate of polymorphic enzyme. Individuals are categorized
as slow, intermediate and fast metabolizers.
Since no IV data were available, relative bioavailability was fixed to 1
for slow metabolizers, and it was found to be 20% lower (and thus 0.8)
in fast and intermediate metabolizers. On top of this difference in
bioavailability, clearance was estimated to be 6, 11 and 14 L/h for
slow, intermediate and fast metabolizers, respectively. The other
clearances and volumes in the model (V, Q, V3) were the same in the
three groups.
Our question is on how to report clearances and volumes for each group
of metabolizers.
Since we only have oral data, we can only estimate oral clearance (e.g.
CL/F), and normally this is what we would like to report, but in our
case this means dividing the values of CL provided by NONMEM for the
different metabolizers by their respective bioavailability. This would
imply reporting 3 different values not only for CL/F, but also for V/F,
Q/F and V3/F, resulting in a over-populated table.
Moreover, since the model contains BSV both in CL and bioavailability,
also the BSV of CL/F should be calculated if we want to report it.
For these reasons, we decided it is best to report the "pure" values of
CL, V, Q and V3 used in the NONMEM model, and then state that, to obtain
CL/F, V/F, Q/F and V3/F, one should divide by the respective
bioavailability. Does this make sense?
If so, how would you indicate the parameters in the table? Calling it
only CL gives the idea that we are providing the value of absolute CL,
which is not possible without IV data. What we are indeed reporting are
the values of CL (or V, Q, V3), if the bioavailability is fixed to a
certain value (1 for slow metabolizers, and 0.8 for intermediate and
fast). Is there a specific name that could be used for that? Would a
simple explanation under the table be acceptable?
What is the experience of the community with this? Any suggestions?
Thank you in advance for your help,
The pharmacometrics group at the University of Cape Town
--
------------------------------------------------
Paolo Denti, PhD
Junior Lecturer
Division of Clinical Pharmacology
Department of Medicine
University of Cape Town
K45 Old Main Building
Groote Schuur Hospital
Observatory, Cape Town
7925 South Africa
phone: +27 21 404 7719
fax: +27 21 448 1989
email: [email protected]
------------------------------------------------
***************************DISCLAIMER****************************
De informatie in dit e-mail bericht is uitsluitend bestemd
voor de geadresseerde. Verstrekking aan en gebruik door
anderen is niet toegestaan. Door de elektronische verzending
van het bericht kunnen er geen rechten worden ontleend aan de
informatie.
Dear Paolo,
I think you are right to report disposition parameters and F separately and
then in the text calculate CL/F and V/F values for comparison with literature,
but I agree with Rob that a mechanistic 'hepatic' model would be worth a try.
If you are concerned about the validity of literature blood flows and since
isoniazid is high extraction ratio drug you could fix CLI to a high number for
the rapid metabolisers and estimate an allometrically scaled apparent hepatic
blood flow with a covariate on CLI for the poor and intermediates. If you were
to centre the allometric blood flow scale on 70kg then a good place to fix CLI
would be something like 1000*(WT/70)**0.75.
BW,
Joe
Joseph F Standing
MRC Fellow, UCL Institute of Child Health
Antimicrobial Pharmacist, Great Ormond Street Hospital
Tel: +44(0)207 905 2370
Mobile: +44(0)7970 572435
Quoted reply history
________________________________________
From: [email protected] [[email protected]] On Behalf Of
Paolo Denti [[email protected]]
Sent: 07 January 2013 15:20
To: [email protected]
Cc: [email protected]
Subject: Re: [NMusers] The theory of relativity for CL and V...
Dear Rob,
thanks for the suggestion.
While a well stirred model could indeed address the issue in a more
mechanistic way, the problem is that we would need estimates of hepatic
blood flow and the patients in the study are malnourished children, some
younger than 3 months of age. I am not sure how reliable the
weight-based formulas for blood flow are in such a population, but it
could be an option to explore.
The drug is isoniazid, and we don't have data on the metabolite, so the
choice of lower bioavailability, besides being plausible, is based
mostly on the NONMEM OFV.
Based on the current parametrisation and model, how would you report the
values?
Thanks again,
Paolo
On 2013/01/07 16:24, [email protected] wrote:
> Dear Paolo,
>
> The reduced bioavailability is most likely a result of increased,
> however variable, pre-systemic metabolism which also correlates with
> systemic clearance. Have you tried linking these together in your model,
> e.g. with a well-stirred liver model (e.g. Gordi et al Br J Clin
> Pharmacol. 2005 Feb;59(2):189-98.)? This would most likely give you a
> more accurate estimation of (relative) bioavailability, and thus
> clearance and volume of distribution in comparison with a model with a
> BSV on CL/F and a separate BSV on F.
>
> Perhaps off-topic: What drug are you studying? Efavirenz? The
> CYP2B6-mediated metabolite 8-hydroxyefavirenz may be easily measured.
> You could investigate whether metabolite data support your hypothesis.
>
> Cheers,
> Rob
>
> ------
> R. ter Heine, PhD, PharmD
> Hospital pharmacist i.t.
> Meander Medical Center, Amersfoort, The Netherlands
> T: +31-33-8502335
> E: [email protected]
>
>
>
> -----Oorspronkelijk bericht-----
> Van: [email protected] [mailto:[email protected]]
> Namens Paolo Denti
> Verzonden: maandag 7 januari 2013 14:19
> Aan: NMusers
> Onderwerp: [NMusers] The theory of relativity for CL and V...
>
> Dear NMusers,
> we have a question we have been debating in our group, we have come to
> an agreement, and we would like the input from the NMusers community. It
> is about how to report values for clearances and volumes when the
> relative bioavailability is fixed to values different from 1 in some of
> the subjects.
>
> We developed a 2 compartment POPK model for an orally administered drug
> that is a substrate of polymorphic enzyme. Individuals are categorized
> as slow, intermediate and fast metabolizers.
>
> Since no IV data were available, relative bioavailability was fixed to 1
> for slow metabolizers, and it was found to be 20% lower (and thus 0.8)
> in fast and intermediate metabolizers. On top of this difference in
> bioavailability, clearance was estimated to be 6, 11 and 14 L/h for
> slow, intermediate and fast metabolizers, respectively. The other
> clearances and volumes in the model (V, Q, V3) were the same in the
> three groups.
>
> Our question is on how to report clearances and volumes for each group
> of metabolizers.
>
> Since we only have oral data, we can only estimate oral clearance (e.g.
> CL/F), and normally this is what we would like to report, but in our
> case this means dividing the values of CL provided by NONMEM for the
> different metabolizers by their respective bioavailability. This would
> imply reporting 3 different values not only for CL/F, but also for V/F,
> Q/F and V3/F, resulting in a over-populated table.
>
> Moreover, since the model contains BSV both in CL and bioavailability,
> also the BSV of CL/F should be calculated if we want to report it.
>
> For these reasons, we decided it is best to report the "pure" values of
> CL, V, Q and V3 used in the NONMEM model, and then state that, to obtain
> CL/F, V/F, Q/F and V3/F, one should divide by the respective
> bioavailability. Does this make sense?
>
> If so, how would you indicate the parameters in the table? Calling it
> only CL gives the idea that we are providing the value of absolute CL,
> which is not possible without IV data. What we are indeed reporting are
> the values of CL (or V, Q, V3), if the bioavailability is fixed to a
> certain value (1 for slow metabolizers, and 0.8 for intermediate and
> fast). Is there a specific name that could be used for that? Would a
> simple explanation under the table be acceptable?
>
> What is the experience of the community with this? Any suggestions?
>
> Thank you in advance for your help,
> The pharmacometrics group at the University of Cape Town
>
> --
> ------------------------------------------------
> Paolo Denti, PhD
> Junior Lecturer
> Division of Clinical Pharmacology
> Department of Medicine
> University of Cape Town
>
> K45 Old Main Building
> Groote Schuur Hospital
> Observatory, Cape Town
> 7925 South Africa
> phone: +27 21 404 7719
> fax: +27 21 448 1989
> email: [email protected]
> ------------------------------------------------
>
>
> ***************************DISCLAIMER****************************
> De informatie in dit e-mail bericht is uitsluitend bestemd
> voor de geadresseerde. Verstrekking aan en gebruik door
> anderen is niet toegestaan. Door de elektronische verzending
> van het bericht kunnen er geen rechten worden ontleend aan de
> informatie.
>
--
------------------------------------------------
Paolo Denti, PhD
Junior Lecturer
Division of Clinical Pharmacology
Department of Medicine
University of Cape Town
K45 Old Main Building
Groote Schuur Hospital
Observatory, Cape Town
7925 South Africa
phone: +27 21 404 7719
fax: +27 21 448 1989
email: [email protected]
------------------------------------------------
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