Dear nmusers,
I am working on a rising single dose study, with 5 cohorts (10, 25,
50, 100 and 200 mg dose groups). This is a oral drug. There are a
total of 45 subjects in the study, 9 subjects in each cohort.
The data fits well to a two compartment model, but at higher doses 100
and 200mg dose groups the concentrations leading to Cmax is
overpredicted significantly that the model seems to be completely
ineffecient in explaining the absorption phase at higher doses.
I have tried using a
Mixture model assuming that there is a sub population with a totally
different absorption, this seemed to work but visual predictive check
failed.
Used a cobination zero and first order absorption model which couldn't
fix the issue at higher doses
Transit compartment model (A flexible approach to modeling variable
absorption in the context of repeated dosing: illustrated with
rifampicin, J. Wilkins, Page 2007). This approach did not work with
NONMEM V.
i assumed that the drug at higher doses has saturable absorption but
even that does not help much.
Can someone please comment on this.
Thanks
Adithya
Absorption
Adithya,
Let the data tell you what model to use/try. Below are things that I
personally looked at before or I've seen colleagues of mine at SPRI try:
Look at linearity of Cmax and AUC (from noncompartmental data). Based on
your description, Cmax is ~ 3-6 folds less than what you expect from
dose proportionality. Does AUC behave the same way? if yes, then your
issue is in F (bioavailability) and may be also absorption rate (ka). If
AUC is linear but Cmax is not then it's an absorption rate issue and not
bioavailability.
If the issue is with rates only, play with Ka (saturable absorption,
different ka with dose (if not an issue), etc).
If the issue is Cmax and AUC with the same magnitude, then you have to
look for a model describing nonlinear F and may be V/F.
If the nonlinearity issue is in Cmax and AUC at different magnitude,
most likely you'll have to have nonlinear models on both F and ka.
Look at tmax, does it shift from e.g. 1hr to 3hr going from lower to
higher doses. Do the PK profiles (at higher doses) look like ones with a
sustained release formulation? Do the peaks for those profiles look more
"flat" compared to the ones at lower doses?
If tmax shifts, you may have gastric emptying/GI transit time playing a
role and you may have to add a time dependency in ka and/or F in
addition to the combined zero/first order models.
Simpler things to try include:
Look at individual V and Cl values, sort by dose group, do you see a
trend? if yes, then you know that NonMem is trying to force the
nonlinearity on V and Cl instead of F and ka:
One thing that a colleague of mine tried at SPRI and worked for him: Fix
V and this will force nonmem to recognize the differences in F and/or ka
between dose groups.
Regards,
Malaz
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Adithya Muralidharan
Sent: Monday, September 03, 2007 5:42 PM
To: [email protected]
Subject: [NMusers] Absorption
Thanks all for replying.
Murad,
I did try to model the effect of dose on bioavailability. I assumed that
the lower doses have a bioavailability of 1 and tried calculating the
bioavailability of higher doses relative to the lower doses. I also
added this effect on absorption rate constant. But the model
predictability at higher doses did not improve much.
I haven't tried an effect of dose as a covariate on volume of
distribution or absorption rate constant, i will try that out.
Stephen,
I tried using saturable absorption as an nonlinear absorption model,
Vmax*A(gut)/Km+A(gut) so at higher doses this becomes zero order and at
lower doses this becomes Vmax/Km *A(gut). This did not help me much. I
was still over predicting the concentrations leading to Cmax by three-6
folds in higher dose groups.
Thanks
Adithya
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This message and any attachments are solely for the
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Dear Adithya,
Your problem has attracted some good advice from the list, but if you are
still interested in trying out the transit model, perhaps we could help,
if you were able to furnish some more details about what exactly went
wrong with your implementation of it in NONMEM V - posted code snippets
and precise error messages would be of particular use.
It ought to be possible to make it work under NMV, although the richer the
data, the better, and NMV is known to be less robust at working with
differential equations than NMVI. Problems can often be resolved with some
minor tweaking, given sufficient information in the data to support the
model - how many observations per individual are you working with, and how
well covered is the absorption phase? You might also try hard-coding the
transit compartments, i.e. not estimating the number as a model parameter,
but fixing it to different values until you find an optimum.
You might also want to take a look at some previous work on the subject,
in which the method was established for single dosing:
Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13 (2004) Abstr 513
[www.page-meeting.org/?abstract=513]
Have you tried normalizing the concentrations by dose and plotting them on
the same axes? That should give you information with respect to whether
you have any dose-related nonlinearity - if the curves for each dose
levels are roughly superimposed, kinetics are linear, and if not, the
relative positions of the curves should provide some useful clues about
what is going on.
Best regards
Justin
Justin Wilkins
Novartis Pharma AG
PH346, MODELING & SIMULATION
CHBS, WSJ-027.1.084
Novartis Pharma AG
Lichtstrasse 35
CH-4056 Basel
Switzerland
Phone: +41 61 324 6549
Fax: +41 61 324 3039
Mobile: +41 76 561 0949
Email : [EMAIL PROTECTED]
"Adithya Muralidharan" <[EMAIL PROTECTED]>
Sent by: [EMAIL PROTECTED]
03.09.2007 19:10
To
[email protected]
cc
Subject
[NMusers] Absorption
Dear nmusers,
I am working on a rising single dose study, with 5 cohorts (10, 25,
50, 100 and 200 mg dose groups). This is a oral drug. There are a
total of 45 subjects in the study, 9 subjects in each cohort.
The data fits well to a two compartment model, but at higher doses 100
and 200mg dose groups the concentrations leading to Cmax is
overpredicted significantly that the model seems to be completely
ineffecient in explaining the absorption phase at higher doses.
I have tried using a
Mixture model assuming that there is a sub population with a totally
different absorption, this seemed to work but visual predictive check
failed.
Used a cobination zero and first order absorption model which couldn't
fix the issue at higher doses
Transit compartment model (A flexible approach to modeling variable
absorption in the context of repeated dosing: illustrated with
rifampicin, J. Wilkins, Page 2007). This approach did not work with
NONMEM V.
i assumed that the drug at higher doses has saturable absorption but
even that does not help much.
Can someone please comment on this.
Thanks
Adithya
Dear Justin,
I did look into dose normalized concentrations-time curve and i do not see
any nonlinearity in PK except for a couple of subjects who appear to be
outliers. I did try to run transit model with FOCE in NM6 but it runs for a
long time and results in terminated message. I did look into Rada's previous
abstarct and tried to use it for single dose but had no luck. I have around
8 observations in the absorption phase and 6 in the elimination phase.I have
mailed you the code i used for my model
Dear Malaz,
Thanks for your tips, i did look into the dose linearity early on the drug
appears to be dose proportional on both AUC and Cmax. There is definitely a
shift in Tmax from 1 hour in lower doses to 6 hours in higher doses but this
drug has low solubility so i assumed that this was inherent characteristic
of the drug so i used a combination Zero-First order model to address this
issue but that was not good enough.
At higher doses i have 3 subjects who have much higher concentrations
leading to Cmax unlike other subjects in the same dose group. I tried to
remove these three subjects to see whether they were impacting the model but
it appears that they have no effect on the model.
I tried fixing volume but even that doesnot answer the anomaly of the model
at higher doses.
This drug is a 3A4 substrate so i am assuming that may be there is a
saturable first pass effect observed at higher doses. In trying to address
this i used a dose varying absorption model as KA=KAMAX*DOSE/KA(50)+DOSE.
when i run with this NONMEM returns to me the same set of intial conditions
in other words the same intial condition value is returned as final
estimate.
Could anyone please advice on how to model saturable first pass effect.
Thanks to all
Adithya
Quoted reply history
On 9/4/07, [EMAIL PROTECTED] <[EMAIL PROTECTED]> wrote:
>
>
> Dear Adithya,
>
> Your problem has attracted some good advice from the list, but if you are
> still interested in trying out the transit model, perhaps we could help, if
> you were able to furnish some more details about what exactly went wrong
> with your implementation of it in NONMEM V - posted code snippets and
> precise error messages would be of particular use.
>
> It ought to be possible to make it work under NMV, although the richer the
> data, the better, and NMV is known to be less robust at working with
> differential equations than NMVI. Problems can often be resolved with some
> minor tweaking, given sufficient information in the data to support the
> model - how many observations per individual are you working with, and how
> well covered is the absorption phase? You might also try hard-coding the
> transit compartments, i.e. not estimating the number as a model parameter,
> but fixing it to different values until you find an optimum.
>
> You might also want to take a look at some previous work on the subject,
> in which the method was established for single dosing:
>
> Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13 (2004) Abstr 513 [
> www.page-meeting.org/?abstract=513]
>
> Have you tried normalizing the concentrations by dose and plotting them on
> the same axes? That should give you information with respect to whether you
> have any dose-related nonlinearity - if the curves for each dose levels are
> roughly superimposed, kinetics are linear, and if not, the relative
> positions of the curves should provide some useful clues about what is going
> on.
>
> Best regards
> Justin
> *Justin Wilkins
> Novartis Pharma AG**
> PH346, MODELING & SIMULATION*
> CHBS, WSJ-027.1.084
> Novartis Pharma AG
> Lichtstrasse 35
> CH-4056 Basel
> Switzerland
> Phone: +41 61 324 6549
> Fax: +41 61 324 3039
> Mobile: +41 76 561 0949
> Email : [EMAIL PROTECTED] <[EMAIL PROTECTED]>
>
>
>
> *"Adithya Muralidharan" <[EMAIL PROTECTED]>*
> Sent by: [EMAIL PROTECTED]
>
> 03.09.2007 19:10
> To
> [email protected] cc
> Subject
> [NMusers] Absorption
>
>
>
>
> Dear nmusers,
>
> I am working on a rising single dose study, with 5 cohorts (10, 25,
> 50, 100 and 200 mg dose groups). This is a oral drug. There are a
> total of 45 subjects in the study, 9 subjects in each cohort.
>
> The data fits well to a two compartment model, but at higher doses 100
> and 200mg dose groups the concentrations leading to Cmax is
> overpredicted significantly that the model seems to be completely
> ineffecient in explaining the absorption phase at higher doses.
>
> I have tried using a
>
> Mixture model assuming that there is a sub population with a totally
> different absorption, this seemed to work but visual predictive check
> failed.
>
> Used a cobination zero and first order absorption model which couldn't
> fix the issue at higher doses
>
> Transit compartment model (A flexible approach to modeling variable
> absorption in the context of repeated dosing: illustrated with
> rifampicin, J. Wilkins, Page 2007). This approach did not work with
> NONMEM V.
>
> i assumed that the drug at higher doses has saturable absorption but
> even that does not help much.
>
> Can someone please comment on this.
>
> Thanks
> Adithya
>
>
Hello Adithya,
You may want to check this article:
Kerbusch T, Wahlby U, Milligan PA, Karlsson MO.
Population pharmacokinetic modelling of darifenacin and its hydroxylated
metabolite using pooled data, incorporating saturable first-pass metabolism,
CYP2D6 genotype and formulation-dependent bioavailability.
Br J Clin Pharmacol. 2003 Dec;56(6):639-52.
Samer
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] on behalf of Adithya Muralidharan
Sent: Tue 04/09/2007 15:25
To: [EMAIL PROTECTED]; [email protected]
Subject: Re: [NMusers] Absorption
Dear Justin,
I did look into dose normalized concentrations-time curve and i do not see
any nonlinearity in PK except for a couple of subjects who appear to be
outliers. I did try to run transit model with FOCE in NM6 but it runs for a
long time and results in terminated message. I did look into Rada's previous
abstarct and tried to use it for single dose but had no luck. I have around
8 observations in the absorption phase and 6 in the elimination phase.I have
mailed you the code i used for my model
Dear Malaz,
Thanks for your tips, i did look into the dose linearity early on the drug
appears to be dose proportional on both AUC and Cmax. There is definitely a
shift in Tmax from 1 hour in lower doses to 6 hours in higher doses but this
drug has low solubility so i assumed that this was inherent characteristic
of the drug so i used a combination Zero-First order model to address this
issue but that was not good enough.
At higher doses i have 3 subjects who have much higher concentrations
leading to Cmax unlike other subjects in the same dose group. I tried to
remove these three subjects to see whether they were impacting the model but
it appears that they have no effect on the model.
I tried fixing volume but even that doesnot answer the anomaly of the model
at higher doses.
This drug is a 3A4 substrate so i am assuming that may be there is a
saturable first pass effect observed at higher doses. In trying to address
this i used a dose varying absorption model as KA=KAMAX*DOSE/KA(50)+DOSE.
when i run with this NONMEM returns to me the same set of intial conditions
in other words the same intial condition value is returned as final
estimate.
Could anyone please advice on how to model saturable first pass effect.
Thanks to all
Adithya
On 9/4/07, [EMAIL PROTECTED] <[EMAIL PROTECTED]> wrote:
>
>
> Dear Adithya,
>
> Your problem has attracted some good advice from the list, but if you are
> still interested in trying out the transit model, perhaps we could help, if
> you were able to furnish some more details about what exactly went wrong
> with your implementation of it in NONMEM V - posted code snippets and
> precise error messages would be of particular use.
>
> It ought to be possible to make it work under NMV, although the richer the
> data, the better, and NMV is known to be less robust at working with
> differential equations than NMVI. Problems can often be resolved with some
> minor tweaking, given sufficient information in the data to support the
> model - how many observations per individual are you working with, and how
> well covered is the absorption phase? You might also try hard-coding the
> transit compartments, i.e. not estimating the number as a model parameter,
> but fixing it to different values until you find an optimum.
>
> You might also want to take a look at some previous work on the subject,
> in which the method was established for single dosing:
>
> Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13 (2004) Abstr 513 [
> www.page-meeting.org/?abstract=513]
>
> Have you tried normalizing the concentrations by dose and plotting them on
> the same axes? That should give you information with respect to whether you
> have any dose-related nonlinearity - if the curves for each dose levels are
> roughly superimposed, kinetics are linear, and if not, the relative
> positions of the curves should provide some useful clues about what is going
> on.
>
> Best regards
> Justin
> *Justin Wilkins
> Novartis Pharma AG**
> PH346, MODELING & SIMULATION*
> CHBS, WSJ-027.1.084
> Novartis Pharma AG
> Lichtstrasse 35
> CH-4056 Basel
> Switzerland
> Phone: +41 61 324 6549
> Fax: +41 61 324 3039
> Mobile: +41 76 561 0949
> Email : [EMAIL PROTECTED] <[EMAIL PROTECTED]>
>
>
>
> *"Adithya Muralidharan" <[EMAIL PROTECTED]>*
> Sent by: [EMAIL PROTECTED]
>
> 03.09.2007 19:10
> To
> [email protected] cc
> Subject
> [NMusers] Absorption
>
>
>
>
> Dear nmusers,
>
> I am working on a rising single dose study, with 5 cohorts (10, 25,
> 50, 100 and 200 mg dose groups). This is a oral drug. There are a
> total of 45 subjects in the study, 9 subjects in each cohort.
>
> The data fits well to a two compartment model, but at higher doses 100
> and 200mg dose groups the concentrations leading to Cmax is
> overpredicted significantly that the model seems to be completely
> ineffecient in explaining the absorption phase at higher doses.
>
> I have tried using a
>
> Mixture model assuming that there is a sub population with a totally
> different absorption, this seemed to work but visual predictive check
> failed.
>
> Used a cobination zero and first order absorption model which couldn't
> fix the issue at higher doses
>
> Transit compartment model (A flexible approach to modeling variable
> absorption in the context of repeated dosing: illustrated with
> rifampicin, J. Wilkins, Page 2007). This approach did not work with
> NONMEM V.
>
> i assumed that the drug at higher doses has saturable absorption but
> even that does not help much.
>
> Can someone please comment on this.
>
> Thanks
> Adithya
>
>
Hi,
If you have a saturable first pass effect, you may want to check this
reference:
Piotrovskij V, Van Peer A. A model with separate hepato-portal compartment
("first-pass" model): fitting to plasma concentration-time profiles in
humans. Pharm Res. 1997 Feb;14(2):230-7.
Best regards,
Juanjo.
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On
Behalf Of Mouksassi Mohamad-Samer
Sent: Tuesday, September 04, 2007 1:35 PM
To: Adithya Muralidharan; [EMAIL PROTECTED];
[email protected]
Subject: RE: [NMusers] Absorption
Hello Adithya,
You may want to check this article:
Kerbusch T, Wahlby U, Milligan PA, Karlsson MO.
Population pharmacokinetic modelling of darifenacin and its hydroxylated
metabolite using pooled data, incorporating saturable first-pass metabolism,
CYP2D6 genotype and formulation-dependent bioavailability.
Br J Clin Pharmacol. 2003 Dec;56(6):639-52.
Samer
-----Original Message-----
From: [EMAIL PROTECTED] on behalf of Adithya Muralidharan
Sent: Tue 04/09/2007 15:25
To: [EMAIL PROTECTED]; [email protected]
Subject: Re: [NMusers] Absorption
Dear Justin,
I did look into dose normalized concentrations-time curve and i do not see
any nonlinearity in PK except for a couple of subjects who appear to be
outliers. I did try to run transit model with FOCE in NM6 but it runs for a
long time and results in terminated message. I did look into Rada's previous
abstarct and tried to use it for single dose but had no luck. I have around
8 observations in the absorption phase and 6 in the elimination phase.I have
mailed you the code i used for my model
Dear Malaz,
Thanks for your tips, i did look into the dose linearity early on the drug
appears to be dose proportional on both AUC and Cmax. There is definitely a
shift in Tmax from 1 hour in lower doses to 6 hours in higher doses but this
drug has low solubility so i assumed that this was inherent characteristic
of the drug so i used a combination Zero-First order model to address this
issue but that was not good enough.
At higher doses i have 3 subjects who have much higher concentrations
leading to Cmax unlike other subjects in the same dose group. I tried to
remove these three subjects to see whether they were impacting the model but
it appears that they have no effect on the model.
I tried fixing volume but even that doesnot answer the anomaly of the model
at higher doses.
This drug is a 3A4 substrate so i am assuming that may be there is a
saturable first pass effect observed at higher doses. In trying to address
this i used a dose varying absorption model as KA=KAMAX*DOSE/KA(50)+DOSE.
when i run with this NONMEM returns to me the same set of intial conditions
in other words the same intial condition value is returned as final
estimate.
Could anyone please advice on how to model saturable first pass effect.
Thanks to all
Adithya
On 9/4/07, [EMAIL PROTECTED] <[EMAIL PROTECTED]> wrote:
>
>
> Dear Adithya,
>
> Your problem has attracted some good advice from the list, but if you are
> still interested in trying out the transit model, perhaps we could help,
if
> you were able to furnish some more details about what exactly went wrong
> with your implementation of it in NONMEM V - posted code snippets and
> precise error messages would be of particular use.
>
> It ought to be possible to make it work under NMV, although the richer the
> data, the better, and NMV is known to be less robust at working with
> differential equations than NMVI. Problems can often be resolved with some
> minor tweaking, given sufficient information in the data to support the
> model - how many observations per individual are you working with, and how
> well covered is the absorption phase? You might also try hard-coding the
> transit compartments, i.e. not estimating the number as a model parameter,
> but fixing it to different values until you find an optimum.
>
> You might also want to take a look at some previous work on the subject,
> in which the method was established for single dosing:
>
> Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13 (2004) Abstr 513 [
> www.page-meeting.org/?abstract=513]
>
> Have you tried normalizing the concentrations by dose and plotting them on
> the same axes? That should give you information with respect to whether
you
> have any dose-related nonlinearity - if the curves for each dose levels
are
> roughly superimposed, kinetics are linear, and if not, the relative
> positions of the curves should provide some useful clues about what is
going
> on.
>
> Best regards
> Justin
> *Justin Wilkins
> Novartis Pharma AG**
> PH346, MODELING & SIMULATION*
> CHBS, WSJ-027.1.084
> Novartis Pharma AG
> Lichtstrasse 35
> CH-4056 Basel
> Switzerland
> Phone: +41 61 324 6549
> Fax: +41 61 324 3039
> Mobile: +41 76 561 0949
> Email : [EMAIL PROTECTED] <[EMAIL PROTECTED]>
>
>
>
> *"Adithya Muralidharan" <[EMAIL PROTECTED]>*
> Sent by: [EMAIL PROTECTED]
>
> 03.09.2007 19:10
> To
> [email protected] cc
> Subject
> [NMusers] Absorption
>
>
>
>
> Dear nmusers,
>
> I am working on a rising single dose study, with 5 cohorts (10, 25,
> 50, 100 and 200 mg dose groups). This is a oral drug. There are a
> total of 45 subjects in the study, 9 subjects in each cohort.
>
> The data fits well to a two compartment model, but at higher doses 100
> and 200mg dose groups the concentrations leading to Cmax is
> overpredicted significantly that the model seems to be completely
> ineffecient in explaining the absorption phase at higher doses.
>
> I have tried using a
>
> Mixture model assuming that there is a sub population with a totally
> different absorption, this seemed to work but visual predictive check
> failed.
>
> Used a cobination zero and first order absorption model which couldn't
> fix the issue at higher doses
>
> Transit compartment model (A flexible approach to modeling variable
> absorption in the context of repeated dosing: illustrated with
> rifampicin, J. Wilkins, Page 2007). This approach did not work with
> NONMEM V.
>
> i assumed that the drug at higher doses has saturable absorption but
> even that does not help much.
>
> Can someone please comment on this.
>
> Thanks
> Adithya
>
>
Malaz,
The reason why i beleive that there might be nonlinearity is beacuse with
the data that we have it is hard for us to say that the drug is dose
proportional. When i looked at logratios of exposure and Cmax they appeared
to be fine. But i would say that we do not have the power to check for dose
proportionality in the current study.
As you say there is substantially large amount of variability in absorption
phase of the drug at higher doses. To address this when i used a mixture
model i tried estimating a separate eta's on each of the KA's but this did
not help much. May be i should follow what sammer mentioned try to model
each and evry dose group separately and see how KA varies with dose.
Thanks
Adithya
Quoted reply history
On 9/4/07, Abutarif, Malaz <[EMAIL PROTECTED]> wrote:
>
> Dear,
> I may be missing something here. If the data is dose proportional for Cmax
> and AUC, why are you trying to fit a nonlinear model in ka and/or F?
> If you have much higher variability (higher CV%) at the higher doses, then
> I would try using a different eta for the higher doses.
>
> A saturable first pass model will mean a nonlinear (higher than expected
> concentrations/exposures) at larger doses. If your data says that you do not
> have higher than dose proportional Cmax and AUC, I don't see why you would
> think there is a satruable first pass?
> Malaz
>
>
> -----Original Message-----
> *From:* [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
> *On Behalf Of *Adithya Muralidharan
> *Sent:* Tuesday, September 04, 2007 3:26 PM
> *To:* [EMAIL PROTECTED]; [email protected]
> *Subject:* Re: [NMusers] Absorption
>
> Dear Justin,
>
> I did look into dose normalized concentrations-time curve and i do not see
> any nonlinearity in PK except for a couple of subjects who appear to be
> outliers. I did try to run transit model with FOCE in NM6 but it runs for a
> long time and results in terminated message. I did look into Rada's previous
> abstarct and tried to use it for single dose but had no luck. I have around
> 8 observations in the absorption phase and 6 in the elimination phase.Ihave
> mailed you the code i used for my model
>
> Dear Malaz,
>
> Thanks for your tips, i did look into the dose linearity early on the drug
> appears to be dose proportional on both AUC and Cmax. There is definitely a
> shift in Tmax from 1 hour in lower doses to 6 hours in higher doses but this
> drug has low solubility so i assumed that this was inherent characteristic
> of the drug so i used a combination Zero-First order model to address this
> issue but that was not good enough.
>
> At higher doses i have 3 subjects who have much higher concentrations
> leading to Cmax unlike other subjects in the same dose group. I tried to
> remove these three subjects to see whether they were impacting the model but
> it appears that they have no effect on the model.
>
> I tried fixing volume but even that doesnot answer the anomaly of the
> model at higher doses.
>
> This drug is a 3A4 substrate so i am assuming that may be there is a
> saturable first pass effect observed at higher doses. In trying to address
> this i used a dose varying absorption model as KA=KAMAX*DOSE/KA(50)+DOSE.
> when i run with this NONMEM returns to me the same set of intial conditions
> in other words the same intial condition value is returned as final
> estimate.
>
> Could anyone please advice on how to model saturable first pass effect.
>
> Thanks to all
> Adithya
>
>
>
>
> On 9/4/07, [EMAIL PROTECTED] <[EMAIL PROTECTED] >
> wrote:
> >
> >
> > Dear Adithya,
> >
> > Your problem has attracted some good advice from the list, but if you
> > are still interested in trying out the transit model, perhaps we could help,
> > if you were able to furnish some more details about what exactly went wrong
> > with your implementation of it in NONMEM V - posted code snippets and
> > precise error messages would be of particular use.
> >
> > It ought to be possible to make it work under NMV, although the richer
> > the data, the better, and NMV is known to be less robust at working with
> > differential equations than NMVI. Problems can often be resolved with some
> > minor tweaking, given sufficient information in the data to support the
> > model - how many observations per individual are you working with, and how
> > well covered is the absorption phase? You might also try hard-coding the
> > transit compartments, i.e. not estimating the number as a model
> > parameter, but fixing it to different values until you find an optimum.
> >
> > You might also want to take a look at some previous work on the subject,
> > in which the method was established for single dosing:
> >
> > Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13 (2004) Abstr 513
> > [www.page-meeting.org/?abstract=513
> > ]
> >
> > Have you tried normalizing the concentrations by dose and plotting them
> > on the same axes? That should give you information with respect to whether
> > you have any dose-related nonlinearity - if the curves for each dose levels
> > are roughly superimposed, kinetics are linear, and if not, the relative
> > positions of the curves should provide some useful clues about what is going
> > on.
> >
> > Best regards
> > Justin
> > *Justin Wilkins
> > Novartis Pharma AG**
> > PH346, MODELING & SIMULATION*
> > CHBS, WSJ-027.1.084
> > Novartis Pharma AG
> > Lichtstrasse 35
> > CH-4056 Basel
> > Switzerland
> > Phone: +41 61 324 6549
> > Fax: +41 61 324 3039
> > Mobile: +41 76 561 0949
> > Email : [EMAIL PROTECTED] <[EMAIL PROTECTED]>
> >
> >
> >
> > *"Adithya Muralidharan" < [EMAIL PROTECTED]>*
> > Sent by: [EMAIL PROTECTED]
> >
> > 03.09.2007 19:10
> > To
> > [email protected] cc
> > Subject
> > [NMusers] Absorption
> >
> >
> >
> >
> > Dear nmusers,
> >
> > I am working on a rising single dose study, with 5 cohorts (10, 25,
> > 50, 100 and 200 mg dose groups). This is a oral drug. There are a
> > total of 45 subjects in the study, 9 subjects in each cohort.
> >
> > The data fits well to a two compartment model, but at higher doses 100
> > and 200mg dose groups the concentrations leading to Cmax is
> > overpredicted significantly that the model seems to be completely
> > ineffecient in explaining the absorption phase at higher doses.
> >
> > I have tried using a
> >
> > Mixture model assuming that there is a sub population with a totally
> > different absorption, this seemed to work but visual predictive check
> > failed.
> >
> > Used a cobination zero and first order absorption model which couldn't
> > fix the issue at higher doses
> >
> > Transit compartment model (A flexible approach to modeling variable
> > absorption in the context of repeated dosing: illustrated with
> > rifampicin, J. Wilkins, Page 2007). This approach did not work with
> > NONMEM V.
> >
> > i assumed that the drug at higher doses has saturable absorption but
> > even that does not help much.
> >
> > Can someone please comment on this.
> >
> > Thanks
> > Adithya
> >
> >
> *********************************************************************
> This message and any attachments are solely for the
> intended recipient. If you are not the intended recipient,
> disclosure, copying, use or distribution of the information
> included in this message is prohibited -- Please
> immediately and permanently delete.
>
>
Hi,
I second Malaz's suggestion. If the Cmax and AUC suggest dose
proportionality and linear PK and the dose normalized plots of
concentration-time profiles are also almost superimposable, then , to me, it
looks like there is no need to try nonlineariry in absorption or
bioavailability terms. You may want to estimate a higher ETA for the the
higher doses or maybe use a different residual variability model for high
vs. low doses (maybe proportioal for low and log for high). If transit
compartment model or any other complex absorption model is not working even
when you remove the problematic profiles, then there is something inherent
in the data that pertains to variability.
How rich is your sampling? Are you sure that you are right on when you
measure Cmax for all individuals. If the slope if the terminal phase is not
that different between dose groups, then maybe saturable elimination won't
help.
I hope this helps.
Murad Melhem,PhD
Cognigen Corporation
Quoted reply history
On 9/5/07, Perez Ruixo, Juan Jose <[EMAIL PROTECTED]> wrote:
>
> Hi,
>
> If you have a saturable first pass effect, you may want to check this
> reference:
>
> Piotrovskij V, Van Peer A. A model with separate hepato-portal compartment
> ("first-pass" model): fitting to plasma concentration-time profiles in
> humans. Pharm Res. 1997 Feb;14(2):230-7.
>
> Best regards,
> Juanjo.
>
> -----Original Message-----
> From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]<[EMAIL PROTECTED]>]
> On Behalf Of Mouksassi Mohamad-Samer
> Sent: Tuesday, September 04, 2007 1:35 PM
> To: Adithya Muralidharan; [EMAIL PROTECTED];
> [email protected]
> Subject: RE: [NMusers] Absorption
>
> Hello Adithya,
>
> You may want to check this article:
>
> Kerbusch T, Wahlby U, Milligan PA, Karlsson MO.
>
> Population pharmacokinetic modelling of darifenacin and its hydroxylated
> metabolite using pooled data, incorporating saturable first-pass metabolism,
> CYP2D6 genotype and formulation-dependent bioavailability.
>
> Br J Clin Pharmacol. 2003 Dec;56(6):639-52.
>
> Samer
>
> -----Original Message-----
> From: [EMAIL PROTECTED] on behalf of Adithya Muralidharan
> Sent: Tue 04/09/2007 15:25
> To: [EMAIL PROTECTED]; [email protected]
> Subject: Re: [NMusers] Absorption
>
> Dear Justin,
>
> I did look into dose normalized concentrations-time curve and i do not see
> any nonlinearity in PK except for a couple of subjects who appear to be
> outliers. I did try to run transit model with FOCE in NM6 but it runs for
> a
> long time and results in terminated message. I did look into Rada's
> previous
> abstarct and tried to use it for single dose but had no luck. I have
> around
> 8 observations in the absorption phase and 6 in the elimination phase.Ihave
> mailed you the code i used for my model
>
> Dear Malaz,
>
> Thanks for your tips, i did look into the dose linearity early on the drug
> appears to be dose proportional on both AUC and Cmax. There is definitely
> a
> shift in Tmax from 1 hour in lower doses to 6 hours in higher doses but
> this
> drug has low solubility so i assumed that this was inherent characteristic
> of the drug so i used a combination Zero-First order model to address this
> issue but that was not good enough.
>
> At higher doses i have 3 subjects who have much higher concentrations
> leading to Cmax unlike other subjects in the same dose group. I tried to
> remove these three subjects to see whether they were impacting the model
> but
> it appears that they have no effect on the model.
>
> I tried fixing volume but even that doesnot answer the anomaly of the
> model
> at higher doses.
>
> This drug is a 3A4 substrate so i am assuming that may be there is a
> saturable first pass effect observed at higher doses. In trying to address
> this i used a dose varying absorption model as KA=KAMAX*DOSE/KA(50)+DOSE.
> when i run with this NONMEM returns to me the same set of intial
> conditions
> in other words the same intial condition value is returned as final
> estimate.
>
> Could anyone please advice on how to model saturable first pass effect.
>
> Thanks to all
> Adithya
>
>
>
> On 9/4/07, [EMAIL PROTECTED] <[EMAIL PROTECTED]>
> wrote:
> >
> >
> > Dear Adithya,
> >
> > Your problem has attracted some good advice from the list, but if you
> are
> > still interested in trying out the transit model, perhaps we could help,
> if
> > you were able to furnish some more details about what exactly went wrong
> > with your implementation of it in NONMEM V - posted code snippets and
> > precise error messages would be of particular use.
> >
> > It ought to be possible to make it work under NMV, although the richer
> the
> > data, the better, and NMV is known to be less robust at working with
> > differential equations than NMVI. Problems can often be resolved with
> some
> > minor tweaking, given sufficient information in the data to support the
> > model - how many observations per individual are you working with, and
> how
> > well covered is the absorption phase? You might also try hard-coding the
> > transit compartments, i.e. not estimating the number as a model
> parameter,
> > but fixing it to different values until you find an optimum.
> >
> > You might also want to take a look at some previous work on the subject,
> > in which the method was established for single dosing:
> >
> > Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13 (2004) Abstr 513 [
> > www.page-meeting.org/?abstract=513]
> >
> > Have you tried normalizing the concentrations by dose and plotting them
> on
> > the same axes? That should give you information with respect to whether
> you
> > have any dose-related nonlinearity - if the curves for each dose levels
> are
> > roughly superimposed, kinetics are linear, and if not, the relative
> > positions of the curves should provide some useful clues about what is
> going
> > on.
> >
> > Best regards
> > Justin
> > *Justin Wilkins
> > Novartis Pharma AG**
> > PH346, MODELING & SIMULATION*
> > CHBS, WSJ-027.1.084
> > Novartis Pharma AG
> > Lichtstrasse 35
> > CH-4056 Basel
> > Switzerland
> > Phone: +41 61 324 6549
> > Fax: +41 61 324 3039
> > Mobile: +41 76 561 0949
> > Email : [EMAIL PROTECTED] <[EMAIL PROTECTED]>
> >
> >
> >
> > *"Adithya Muralidharan" <[EMAIL PROTECTED]>*
> > Sent by: [EMAIL PROTECTED]
> >
> > 03.09.2007 19:10
> > To
> > [email protected] cc
> > Subject
> > [NMusers] Absorption
> >
> >
> >
> >
> > Dear nmusers,
> >
> > I am working on a rising single dose study, with 5 cohorts (10, 25,
> > 50, 100 and 200 mg dose groups). This is a oral drug. There are a
> > total of 45 subjects in the study, 9 subjects in each cohort.
> >
> > The data fits well to a two compartment model, but at higher doses 100
> > and 200mg dose groups the concentrations leading to Cmax is
> > overpredicted significantly that the model seems to be completely
> > ineffecient in explaining the absorption phase at higher doses.
> >
> > I have tried using a
> >
> > Mixture model assuming that there is a sub population with a totally
> > different absorption, this seemed to work but visual predictive check
> > failed.
> >
> > Used a cobination zero and first order absorption model which couldn't
> > fix the issue at higher doses
> >
> > Transit compartment model (A flexible approach to modeling variable
> > absorption in the context of repeated dosing: illustrated with
> > rifampicin, J. Wilkins, Page 2007). This approach did not work with
> > NONMEM V.
> >
> > i assumed that the drug at higher doses has saturable absorption but
> > even that does not help much.
> >
> > Can someone please comment on this.
> >
> > Thanks
> > Adithya
> >
> >
>
>