Dear nmusers,
I would like to model PK profiles of a compounds which mostly distributes in
blood volume. The subjects which were investigated underwent hemodialysis for
approx. the first three hours after infusion start, and the compound was given
over a time period of ~5-10 min.
It is well known that during hemodialysis, blood volume changes. Therefore, I
would like to add a dynamic component to the central volume parameter, allowing
it to decrease during hemodialysis and then to reincrease after dialysis has
ended. I have all information about start and end time of both dosing and
dialysis. Individual times between subjects differed. Unfortunately, I have not
been creative enough to come up with a NONMEM code that can do this. Could any
of you help out?
Also, I probably do not have late enough time points to estimate when exactly
blood volume would be restored. Does anyone know how much time the body needs
after dialysis has ended until it is back to the original blood volume?
Thanks for your help and best
Nele
______________________________________________________________
Dr. Nele Käßner
Principal Scientist Modeling and Simulation
Global Pharmacometrics
Experimental Medicine
Takeda Pharmaceuticals International GmbH
Thurgauerstrasse 130
8152 Glattpark-Opfikon (Zürich)
Switzerland
Visitor address:
Alpenstrasse 3
8152 Glattpark-Opfikon (Zürich)
Switzerland
Phone: (+41) 44 / 55 51 404
Mobile: (+41) 79 / 654 33 99
mailto: [email protected]<mailto:[email protected]>
http://www.takeda.com
--------------------------------------------------------------------
The content of this email and of any files transmitted may contain
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how to model blood volume change during and after hemodialysis?
Hello,
In terms of how long it takes to restore blood volume, i think it should be
immediate because they usually give fluids during the dialysis to replace lost
blood volume. Otherwise, there will be a significant drop in BP. You may have
the volumes of fluid given in the patient charts if you have that.
In terms of changing volume you can do that in two ways:
1. If you have serial measurements of patient body weight, you can link that to
volume as a covariate and it will change with change in weight (time-varying
covariate). But this needs hourly or even more frequent weight measurements.
2. You can model the change in volume with time using a simple linear slope
model where volume decreases with time during dialysis and increases with time
after dialysis and estimate the slope for each process. However, i think this
will be difficult to estimate separate from changes in clearance and the slope
estimates you get will just be arbitrary. If you have samples from dialysate,
it might be better.
I hope this helps.
Quoted reply history
----- Original Message -----
From: "Nele Kaessner" <[email protected]>
To: [email protected]
Sent: Friday, January 18, 2013 8:24:05 AM
Subject: [NMusers] how to model blood volume change during and after
hemodialysis?
Dear nmusers,
I would like to model PK profiles of a compounds which mostly distributes in
blood volume. The subjects which were investigated underwent hemodialysis for
approx. the first three hours after infusion start, and the compound was given
over a time period of ~5-10 min.
It is well known that during hemodialysis, blood volume changes. Therefore, I
would like to add a dynamic component to the central volume parameter, allowing
it to decrease during hemodialysis and then to reincrease after dialysis has
ended. I have all information about start and end time of both dosing and
dialysis. Individual times between subjects differed. Unfortunately, I have not
been creative enough to come up with a NONMEM code that can do this. Could any
of you help out?
Also, I probably do not have late enough time points to estimate when exactly
blood volume would be restored. Does anyone know how much time the body needs
after dialysis has ended until it is back to the original blood volume?
Thanks for your help and best
Nele
______________________________________________________________
Dr. Nele Käßner
Principal Scientist Modeling and Simulation
Global Pharmacometrics
Experimental Medicine
Takeda Pharmaceuticals International GmbH
Thurgauerstrasse 130
8152 Glattpark-Opfikon (Zürich)
Switzerland
Visitor address:
Alpenstrasse 3
8152 Glattpark-Opfikon (Zürich)
Switzerland
Phone: (+41) 44 / 55 51 404
Mobile: (+41) 79 / 654 33 99
mailto: [email protected]
http://www.takeda.com
--------------------------------------------------------------------
The content of this email and of any files transmitted may contain
confidential, proprietary or legally privileged information and is intended
solely for the use of the person/s or entity/ies to whom it is addressed. If
you have received this email in error you have no permission whatsoever to use,
copy, disclose or forward all or any of its contents. Please immediately notify
the sender and thereafter delete this email and any attachments.
Nele,
You can use T in $DES block if you use ADVAN6, 8, 9, or 13 and write you system in differential equations
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
Quoted reply history
On 1/18/2013 10:12 AM, Kaessner, Nele wrote:
> Dear Ahmed and all,
>
> First of all, thank you for your response.
> The reason I believe that blood volume is altered is because I see an increase
> in concentrations until the end of hemodialysis, despite the fact that compound
> infusion ended two hours earlier. I would want to estimate the decreasing
> volume using information from both subjects with and without hemodialysis (for
> those without dialysis, concentrations drop as expected after the end of the
> infusion). Clearance via hemodialysis is not a problem by the way, compound is
> too big :-)
> My problem mostly relates to the coding in NONMEM. How do I model a continuous
> change in V1 over time? $PK does not allow the variable 'T' to be used, and I
> don't just want to use TIME, as this would only consider time points actually
> contained in the data set.
> Any suggestions?
>
> Thank you and best regards
> Nele
> ______________________________________________________________
>
> Dr. Nele Käßner
> Principal Scientist Modeling and Simulation
> Global Pharmacometrics
> Experimental Medicine
>
> Takeda Pharmaceuticals International GmbH
> Thurgauerstrasse 130
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
>
> Visitor address:
> Alpenstrasse 3
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
>
> Phone: (+41) 44 / 55 51 404
> Mobile: (+41) 79 / 654 33 99
>
> mailto: [email protected]
> http://www.takeda.com
>
> -----Original Message-----
> From: Ahmed N Mohamed [mailto:[email protected]]
> Sent: Freitag, 18. Januar 2013 3:28
> To: Kaessner, Nele
> Cc: [email protected]
> Subject: Re: [NMusers] how to model blood volume change during and after
> hemodialysis?
>
> Hello,
>
> In terms of how long it takes to restore blood volume, i think it should be
> immediate because they usually give fluids during the dialysis to replace lost
> blood volume. Otherwise, there will be a significant drop in BP. You may have
> the volumes of fluid given in the patient charts if you have that.
>
> In terms of changing volume you can do that in two ways:
> 1. If you have serial measurements of patient body weight, you can link that to
> volume as a covariate and it will change with change in weight (time-varying
> covariate). But this needs hourly or even more frequent weight measurements.
>
> 2. You can model the change in volume with time using a simple linear slope
> model where volume decreases with time during dialysis and increases with time
> after dialysis and estimate the slope for each process. However, i think this
> will be difficult to estimate separate from changes in clearance and the slope
> estimates you get will just be arbitrary. If you have samples from dialysate,
> it might be better.
>
> I hope this helps.
>
> ----- Original Message -----
> From: "Nele Kaessner" <[email protected]>
> To: [email protected]
> Sent: Friday, January 18, 2013 8:24:05 AM
> Subject: [NMusers] how to model blood volume change during and after
> hemodialysis?
>
> Dear nmusers,
>
> I would like to model PK profiles of a compounds which mostly distributes in
> blood volume. The subjects which were investigated underwent hemodialysis for
> approx. the first three hours after infusion start, and the compound was given
> over a time period of ~5-10 min.
>
> It is well known that during hemodialysis, blood volume changes. Therefore, I
> would like to add a dynamic component to the central volume parameter, allowing
> it to decrease during hemodialysis and then to reincrease after dialysis has
> ended. I have all information about start and end time of both dosing and
> dialysis. Individual times between subjects differed. Unfortunately, I have not
> been creative enough to come up with a NONMEM code that can do this. Could any
> of you help out?
>
> Also, I probably do not have late enough time points to estimate when exactly
> blood volume would be restored. Does anyone know how much time the body needs
> after dialysis has ended until it is back to the original blood volume?
>
> Thanks for your help and best
>
> Nele
>
> ______________________________________________________________
>
> Dr. Nele Käßner
>
> Principal Scientist Modeling and Simulation
>
> Global Pharmacometrics
>
> Experimental Medicine
>
> Takeda Pharmaceuticals International GmbH
>
> Thurgauerstrasse 130
>
> 8152 Glattpark-Opfikon (Zürich)
>
> Switzerland
>
> Visitor address:
>
> Alpenstrasse 3
>
> 8152 Glattpark-Opfikon (Zürich)
>
> Switzerland
>
> Phone: (+41) 44 / 55 51 404
>
> Mobile: (+41) 79 / 654 33 99
>
> mailto: [email protected]
>
> http://www.takeda.com
>
> --------------------------------------------------------------------
>
> The content of this email and of any files transmitted may contain
> confidential, proprietary or legally privileged information and is intended
> solely for the use of the person/s or entity/ies to whom it is addressed. If
> you have received this email in error you have no permission whatsoever to use,
> copy, disclose or forward all or any of its contents. Please immediately notify
> the sender and thereafter delete this email and any attachments.
>
> --------------------------------------------------------------------
>
> --------------------------------------------------------------------
>
> The content of this email and of any files transmitted may contain
> confidential, proprietary or legally privileged information and is intended
> solely for the use of the person/s or entity/ies to whom it is addressed. If
> you have received this email in error you have no permission whatsoever to use,
> copy, disclose or forward all or any of its contents. Please immediately notify
> the sender and thereafter delete this email and any attachments.
>
>
Dear Nele,
You can use T if you just re-write the model using $DES and ADVAN13.
What is slightly unusual and quite nice about dialysis volume changes is that you can model them with just one additional parameter. This fortunate situation arises because you know the times of dialysis (hopefully precisely). In-between dialysis occasions the plasma volume rises, as most subjects must/will consume more water than they can excrete, and then plasma volume falls back to the baseline during dialysis. So all you need to do is define you central volume as V1 (usually immediately post-dialysis) and then an additional parameter V1acc which is the impact of V1 on the additional accumulation of fluid per day since the last dialysis, so it has units of L/day, and multiply by the time since the last dialysis finished. Provided dialysis is completed, you can generally assume that all of V1acc*days is removed at an approximately linear rate during dialysis. This model can account for differences in dialysis schedule (e.g. weekends) and you can put a random effect on V1acc to account for differences in fluid accumulation between different patients.
It's not perfect, but it is simple. Usually, peripheral volumes are less sensitive to body water so you don't see anything on these. This simple model can often be successfully superimposed on a dialysis clearance model.
Best regards, James
Quoted reply history
On 18/01/2013 15:12, Kaessner, Nele wrote:
> Dear Ahmed and all,
>
> First of all, thank you for your response.
> The reason I believe that blood volume is altered is because I see an increase
> in concentrations until the end of hemodialysis, despite the fact that compound
> infusion ended two hours earlier. I would want to estimate the decreasing
> volume using information from both subjects with and without hemodialysis (for
> those without dialysis, concentrations drop as expected after the end of the
> infusion). Clearance via hemodialysis is not a problem by the way, compound is
> too big :-)
> My problem mostly relates to the coding in NONMEM. How do I model a continuous
> change in V1 over time? $PK does not allow the variable 'T' to be used, and I
> don't just want to use TIME, as this would only consider time points actually
> contained in the data set.
> Any suggestions?
>
> Thank you and best regards
> Nele
> ______________________________________________________________
>
> Dr. Nele Käßner
>
> Principal Scientist Modeling and Simulation
> Global Pharmacometrics
> Experimental Medicine
>
> Takeda Pharmaceuticals International GmbH
>
> Thurgauerstrasse 130
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
>
> Visitor address:
> Alpenstrasse 3
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
>
> Phone: (+41) 44 / 55 51 404
> Mobile: (+41) 79 / 654 33 99
>
> mailto: [email protected]
>
> http://www.takeda.com
>
> -----Original Message-----
> From: Ahmed N Mohamed [mailto:[email protected]]
> Sent: Freitag, 18. Januar 2013 3:28
> To: Kaessner, Nele
> Cc: [email protected]
> Subject: Re: [NMusers] how to model blood volume change during and after
> hemodialysis?
>
> Hello,
>
> In terms of how long it takes to restore blood volume, i think it should be
> immediate because they usually give fluids during the dialysis to replace lost
> blood volume. Otherwise, there will be a significant drop in BP. You may have
> the volumes of fluid given in the patient charts if you have that.
>
> In terms of changing volume you can do that in two ways:
> 1. If you have serial measurements of patient body weight, you can link that to
> volume as a covariate and it will change with change in weight (time-varying
> covariate). But this needs hourly or even more frequent weight measurements.
>
> 2. You can model the change in volume with time using a simple linear slope
> model where volume decreases with time during dialysis and increases with time
> after dialysis and estimate the slope for each process. However, i think this
> will be difficult to estimate separate from changes in clearance and the slope
> estimates you get will just be arbitrary. If you have samples from dialysate,
> it might be better.
>
> I hope this helps.
>
> ----- Original Message -----
> From: "Nele Kaessner" <[email protected]>
> To: [email protected]
> Sent: Friday, January 18, 2013 8:24:05 AM
> Subject: [NMusers] how to model blood volume change during and after
> hemodialysis?
>
> Dear nmusers,
>
> I would like to model PK profiles of a compounds which mostly distributes in
> blood volume. The subjects which were investigated underwent hemodialysis for
> approx. the first three hours after infusion start, and the compound was given
> over a time period of ~5-10 min.
>
> It is well known that during hemodialysis, blood volume changes. Therefore, I
> would like to add a dynamic component to the central volume parameter, allowing
> it to decrease during hemodialysis and then to reincrease after dialysis has
> ended. I have all information about start and end time of both dosing and
> dialysis. Individual times between subjects differed. Unfortunately, I have not
> been creative enough to come up with a NONMEM code that can do this. Could any
> of you help out?
>
> Also, I probably do not have late enough time points to estimate when exactly
> blood volume would be restored. Does anyone know how much time the body needs
> after dialysis has ended until it is back to the original blood volume?
>
> Thanks for your help and best
>
> Nele
>
> ______________________________________________________________
>
> Dr. Nele Käßner
>
> Principal Scientist Modeling and Simulation
>
> Global Pharmacometrics
>
> Experimental Medicine
>
> Takeda Pharmaceuticals International GmbH
>
> Thurgauerstrasse 130
>
> 8152 Glattpark-Opfikon (Zürich)
>
> Switzerland
>
> Visitor address:
>
> Alpenstrasse 3
>
> 8152 Glattpark-Opfikon (Zürich)
>
> Switzerland
>
> Phone: (+41) 44 / 55 51 404
>
> Mobile: (+41) 79 / 654 33 99
>
> mailto: [email protected]
>
> http://www.takeda.com
>
> --------------------------------------------------------------------
>
> The content of this email and of any files transmitted may contain
> confidential, proprietary or legally privileged information and is intended
> solely for the use of the person/s or entity/ies to whom it is addressed. If
> you have received this email in error you have no permission whatsoever to use,
> copy, disclose or forward all or any of its contents. Please immediately notify
> the sender and thereafter delete this email and any attachments.
>
> --------------------------------------------------------------------
>
> --------------------------------------------------------------------
>
> The content of this email and of any files transmitted may contain
> confidential, proprietary or legally privileged information and is intended
> solely for the use of the person/s or entity/ies to whom it is addressed. If
> you have received this email in error you have no permission whatsoever to use,
> copy, disclose or forward all or any of its contents. Please immediately notify
> the sender and thereafter delete this email and any attachments.
>
> --------------------------------------------------------------------
--
James G Wright PhD,
Scientist, Wright Dose Ltd
Tel: UK (0)772 5636914
Dear Nele,
You have to place T under $DES to be continuous and not the discrete time
points from the dataset.
Regards,
Stefaan
-----Oorspronkelijk bericht-----
Quoted reply history
Van: [email protected] [mailto:[email protected]] Namens
Kaessner, Nele
Verzonden: vrijdag 18 januari 2013 16:13
Aan: Ahmed N Mohamed
CC: [email protected]
Onderwerp: RE: [NMusers] how to model blood volume change during and after
hemodialysis?
Dear Ahmed and all,
First of all, thank you for your response.
The reason I believe that blood volume is altered is because I see an increase
in concentrations until the end of hemodialysis, despite the fact that compound
infusion ended two hours earlier. I would want to estimate the decreasing
volume using information from both subjects with and without hemodialysis (for
those without dialysis, concentrations drop as expected after the end of the
infusion). Clearance via hemodialysis is not a problem by the way, compound is
too big :-)
My problem mostly relates to the coding in NONMEM. How do I model a continuous
change in V1 over time? $PK does not allow the variable 'T' to be used, and I
don't just want to use TIME, as this would only consider time points actually
contained in the data set.
Any suggestions?
Thank you and best regards
Nele
______________________________________________________________
Dr. Nele Käßner
Principal Scientist Modeling and Simulation
Global Pharmacometrics
Experimental Medicine
Takeda Pharmaceuticals International GmbH
Thurgauerstrasse 130
8152 Glattpark-Opfikon (Zürich)
Switzerland
Visitor address:
Alpenstrasse 3
8152 Glattpark-Opfikon (Zürich)
Switzerland
Phone: (+41) 44 / 55 51 404
Mobile: (+41) 79 / 654 33 99
mailto: [email protected]
http://www.takeda.com
-----Original Message-----
From: Ahmed N Mohamed [mailto:[email protected]]
Sent: Freitag, 18. Januar 2013 3:28
To: Kaessner, Nele
Cc: [email protected]
Subject: Re: [NMusers] how to model blood volume change during and after
hemodialysis?
Hello,
In terms of how long it takes to restore blood volume, i think it should be
immediate because they usually give fluids during the dialysis to replace lost
blood volume. Otherwise, there will be a significant drop in BP. You may have
the volumes of fluid given in the patient charts if you have that.
In terms of changing volume you can do that in two ways:
1. If you have serial measurements of patient body weight, you can link that to
volume as a covariate and it will change with change in weight (time-varying
covariate). But this needs hourly or even more frequent weight measurements.
2. You can model the change in volume with time using a simple linear slope
model where volume decreases with time during dialysis and increases with time
after dialysis and estimate the slope for each process. However, i think this
will be difficult to estimate separate from changes in clearance and the slope
estimates you get will just be arbitrary. If you have samples from dialysate,
it might be better.
I hope this helps.
----- Original Message -----
From: "Nele Kaessner" <[email protected]>
To: [email protected]
Sent: Friday, January 18, 2013 8:24:05 AM
Subject: [NMusers] how to model blood volume change during and after
hemodialysis?
Dear nmusers,
I would like to model PK profiles of a compounds which mostly distributes in
blood volume. The subjects which were investigated underwent hemodialysis for
approx. the first three hours after infusion start, and the compound was given
over a time period of ~5-10 min.
It is well known that during hemodialysis, blood volume changes. Therefore, I
would like to add a dynamic component to the central volume parameter, allowing
it to decrease during hemodialysis and then to reincrease after dialysis has
ended. I have all information about start and end time of both dosing and
dialysis. Individual times between subjects differed. Unfortunately, I have not
been creative enough to come up with a NONMEM code that can do this. Could any
of you help out?
Also, I probably do not have late enough time points to estimate when exactly
blood volume would be restored. Does anyone know how much time the body needs
after dialysis has ended until it is back to the original blood volume?
Thanks for your help and best
Nele
______________________________________________________________
Dr. Nele Käßner
Principal Scientist Modeling and Simulation
Global Pharmacometrics
Experimental Medicine
Takeda Pharmaceuticals International GmbH
Thurgauerstrasse 130
8152 Glattpark-Opfikon (Zürich)
Switzerland
Visitor address:
Alpenstrasse 3
8152 Glattpark-Opfikon (Zürich)
Switzerland
Phone: (+41) 44 / 55 51 404
Mobile: (+41) 79 / 654 33 99
mailto: [email protected]
http://www.takeda.com
--------------------------------------------------------------------
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solely for the use of the person/s or entity/ies to whom it is addressed. If
you have received this email in error you have no permission whatsoever to use,
copy, disclose or forward all or any of its contents. Please immediately notify
the sender and thereafter delete this email and any attachments.
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Hi James, dear all,
Thanks for your answer. I have understood what you were writing, however I
still have problems to implement the suggestions in NONMEM. This is mainly due
to the somewhat inflexible way NONMEM works. My problems are the following:
• The final V1 needs to be defined in $DES, as otherwise I cannot use T
• V1 is used as a scaling factor to determine concentration. This would
normally be done in $PK, where I cannot use parameters that are defined in $DES
• Y and IPRED are calculated using A(1) and V1, but again $ERROR does not
allow the use of T. My code circumvents this now by using TIME in $ERROR and T
in $DES, but I don't like the solution of defining everything twice.
• Basically, my major issue is that I can use T in $DES, but any PK
parameter I calculate from this can then not be used in $PK or $ERROR, where I
would actually need this. I am sure there must be a solution, but I cannot see
it…
• Additional problem: My code only allows for continuous volume decrease
over the first hemodialysis session. Also, after dialysis it jumps directly
back to the volume that I had before dialysis. What I would like to model
instead would be a continuous drop in volume over dialysis, and then a
reincrease to pre-dialysis levels over the next ~2h. You mentioned a linear
rate after dialysis. How do you implement this? Any suggestions, preferably in
NONMEM code?
What I have right now:
$SUBROUTINE ADVAN13 TOL=5
$MODEL NCOMP=2
COMP=(CENTRAL)
COMP=(PERIPH)
; ----------------[ Structural Model ]----------------
$PK
TVVM=THETA(1)
VM=TVVM*EXP(ETA(1))
TVKM=THETA(2)
KM=TVKM
TVV1=THETA(3)
VC=TVV1*EXP(ETA(2))
TVQ=THETA(4)
Q=TVQ
TVV2=THETA(5)
V2=TVV2
TVCL=THETA(6)
CL=TVCL
TVVAC=THETA(7)
V1ACC=TVVAC
; ----------------[ Error Model ]----------------
$ERROR
;parameter to describe volume decrease over dialysis
VEDD=V1ACC
;after dialysis end (3h) volume back to higher levels
IF (TIME.GT.3) VEDD=0
VD1=VC -VEDD*TIME ;I would like to use T, but get an error message if I do
CE1=A(1)/VD1
IPRED=CE1
DEL=0
IF (IPRED.EQ.0) DEL=0.01
W=CE1
IRES=DV-IPRED
IWRES=IRES/(W+DEL)
Y=CE1+CE1*ERR(1)
;----------------[differential equations]-------------
$DES
VADD=V1ACC
IF (T.GT.3) VADD=0
V1=VC-VADD*T
;Scaling needed to be shifted from $PK as it uses V1
S1=V1
K12=Q/V1
K21=Q/V2
K10=CL/V1
DADT(1) = - K12*A(1) + K21*A(2) - A(1)*VM/(KM+A(1)) -K10*A(1)
DADT(2) = K12*A(1) - K21*A(2)
Thanks again for your help. It is very much appreciated!
Best
Nele
______________________________________________________________
Dr. Nele Käßner
Principal Scientist Modeling and Simulation
Global Pharmacometrics
Experimental Medicine
Takeda Pharmaceuticals International GmbH
Thurgauerstrasse 130
8152 Glattpark-Opfikon (Zürich)
Switzerland
Visitor address:
Alpenstrasse 3
8152 Glattpark-Opfikon (Zürich)
Switzerland
Phone: (+41) 44 / 55 51 404
Mobile: (+41) 79 / 654 33 99
mailto: [email protected]
http://www.takeda.com
Quoted reply history
-----Original Message-----
From: James G Wright [mailto:[email protected]]
Sent: Freitag, 18. Januar 2013 5:10
To: Kaessner, Nele
Cc: Ahmed N Mohamed; [email protected]
Subject: Re: [NMusers] how to model blood volume change during and after
hemodialysis?
Dear Nele,
You can use T if you just re-write the model using $DES and ADVAN13.
What is slightly unusual and quite nice about dialysis volume changes is
that you can model them with just one additional parameter. This
fortunate situation arises because you know the times of dialysis
(hopefully precisely). In-between dialysis occasions the plasma volume
rises, as most subjects must/will consume more water than they can
excrete, and then plasma volume falls back to the baseline during
dialysis. So all you need to do is define you central volume as V1
(usually immediately post-dialysis) and then an additional parameter
V1acc which is the impact of V1 on the additional accumulation of fluid
per day since the last dialysis, so it has units of L/day, and multiply
by the time since the last dialysis finished. Provided dialysis is
completed, you can generally assume that all of V1acc*days is removed at
an approximately linear rate during dialysis. This model can account
for differences in dialysis schedule (e.g. weekends) and you can put a
random effect on V1acc to account for differences in fluid accumulation
between different patients.
It's not perfect, but it is simple. Usually, peripheral volumes are
less sensitive to body water so you don't see anything on these. This
simple model can often be successfully superimposed on a dialysis
clearance model.
Best regards, James
On 18/01/2013 15:12, Kaessner, Nele wrote:
> Dear Ahmed and all,
>
> First of all, thank you for your response.
> The reason I believe that blood volume is altered is because I see an
> increase in concentrations until the end of hemodialysis, despite the fact
> that compound infusion ended two hours earlier. I would want to estimate the
> decreasing volume using information from both subjects with and without
> hemodialysis (for those without dialysis, concentrations drop as expected
> after the end of the infusion). Clearance via hemodialysis is not a problem
> by the way, compound is too big :-)
> My problem mostly relates to the coding in NONMEM. How do I model a
> continuous change in V1 over time? $PK does not allow the variable 'T' to be
> used, and I don't just want to use TIME, as this would only consider time
> points actually contained in the data set.
> Any suggestions?
>
> Thank you and best regards
> Nele
> ______________________________________________________________
>
> Dr. Nele Käßner
> Principal Scientist Modeling and Simulation
> Global Pharmacometrics
> Experimental Medicine
>
> Takeda Pharmaceuticals International GmbH
> Thurgauerstrasse 130
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
>
> Visitor address:
> Alpenstrasse 3
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
>
> Phone: (+41) 44 / 55 51 404
> Mobile: (+41) 79 / 654 33 99
>
> mailto: [email protected]
> http://www.takeda.com
>
>
> -----Original Message-----
> From: Ahmed N Mohamed [mailto:[email protected]]
> Sent: Freitag, 18. Januar 2013 3:28
> To: Kaessner, Nele
> Cc: [email protected]
> Subject: Re: [NMusers] how to model blood volume change during and after
> hemodialysis?
>
> Hello,
>
> In terms of how long it takes to restore blood volume, i think it should be
> immediate because they usually give fluids during the dialysis to replace
> lost blood volume. Otherwise, there will be a significant drop in BP. You may
> have the volumes of fluid given in the patient charts if you have that.
>
> In terms of changing volume you can do that in two ways:
> 1. If you have serial measurements of patient body weight, you can link that
> to volume as a covariate and it will change with change in weight
> (time-varying covariate). But this needs hourly or even more frequent weight
> measurements.
>
> 2. You can model the change in volume with time using a simple linear slope
> model where volume decreases with time during dialysis and increases with
> time after dialysis and estimate the slope for each process. However, i think
> this will be difficult to estimate separate from changes in clearance and the
> slope estimates you get will just be arbitrary. If you have samples from
> dialysate, it might be better.
>
> I hope this helps.
>
> ----- Original Message -----
> From: "Nele Kaessner" <[email protected]>
> To: [email protected]
> Sent: Friday, January 18, 2013 8:24:05 AM
> Subject: [NMusers] how to model blood volume change during and after
> hemodialysis?
>
>
>
>
> Dear nmusers,
>
>
>
> I would like to model PK profiles of a compounds which mostly distributes in
> blood volume. The subjects which were investigated underwent hemodialysis for
> approx. the first three hours after infusion start, and the compound was
> given over a time period of ~5-10 min.
>
> It is well known that during hemodialysis, blood volume changes. Therefore, I
> would like to add a dynamic component to the central volume parameter,
> allowing it to decrease during hemodialysis and then to reincrease after
> dialysis has ended. I have all information about start and end time of both
> dosing and dialysis. Individual times between subjects differed.
> Unfortunately, I have not been creative enough to come up with a NONMEM code
> that can do this. Could any of you help out?
>
> Also, I probably do not have late enough time points to estimate when exactly
> blood volume would be restored. Does anyone know how much time the body needs
> after dialysis has ended until it is back to the original blood volume?
>
>
>
> Thanks for your help and best
>
> Nele
>
> ______________________________________________________________
>
>
>
> Dr. Nele Käßner
>
> Principal Scientist Modeling and Simulation
>
> Global Pharmacometrics
>
> Experimental Medicine
>
>
>
> Takeda Pharmaceuticals International GmbH
>
> Thurgauerstrasse 130
>
> 8152 Glattpark-Opfikon (Zürich)
>
> Switzerland
>
>
>
> Visitor address:
>
> Alpenstrasse 3
>
> 8152 Glattpark-Opfikon (Zürich)
>
> Switzerland
>
>
>
> Phone: (+41) 44 / 55 51 404
>
> Mobile: (+41) 79 / 654 33 99
>
>
>
> mailto: [email protected]
>
> http://www.takeda.com
>
> --------------------------------------------------------------------
>
> The content of this email and of any files transmitted may contain
> confidential, proprietary or legally privileged information and is intended
> solely for the use of the person/s or entity/ies to whom it is addressed. If
> you have received this email in error you have no permission whatsoever to
> use, copy, disclose or forward all or any of its contents. Please immediately
> notify the sender and thereafter delete this email and any attachments.
>
> --------------------------------------------------------------------
>
> --------------------------------------------------------------------
>
> The content of this email and of any files transmitted may contain
> confidential, proprietary or legally privileged information and is intended
> solely for the use of the person/s or entity/ies to whom it is addressed. If
> you have received this email in error you have no permission whatsoever to
> use, copy, disclose or forward all or any of its contents. Please immediately
> notify the sender and thereafter delete this email and any attachments.
>
> --------------------------------------------------------------------
>
--
James G Wright PhD,
Scientist, Wright Dose Ltd
Tel: UK (0)772 5636914
--------------------------------------------------------------------
The content of this email and of any files transmitted may contain
confidential, proprietary or legally privileged information and is intended
solely for the use of the person/s or entity/ies to whom it is addressed. If
you have received this email in error you have no permission whatsoever to use,
copy, disclose or forward all or any of its contents. Please immediately notify
the sender and thereafter delete this email and any attachments.
Dear Nele,
You are on the right track, it is just the NONMEM coding you need to work out. Unfortunately, I have a lot of work on this week so I won't have time to go through this, but it is very likely you will get excellent answers from other people on the list.
The only tip I would give is it is usually easier to code the dialysis as a covariate in the dataset than manually put the times in the code. Watch out though as NONMEM usually backward imputes covariates (so you set your dialysis covariate to 0 at the start of dialysis and 1 at the end to get the correct profile).
Good luck with the idiosyncracies of NONMEM! Kind regards, James
Quoted reply history
On 21/01/2013 09:21, Kaessner, Nele wrote:
> Hi James, dear all,
>
> Thanks for your answer. I have understood what you were writing, however I still have problems to implement the suggestions in NONMEM. This is mainly due to the somewhat inflexible way NONMEM works. My problems are the following:
>
> * The final V1 needs to be defined in $DES, as otherwise I cannot use T
> * V1 is used as a scaling factor to determine concentration. This
> would normally be done in $PK, where I cannot use parameters that
> are defined in $DES
> * Y and IPRED are calculated using A(1) and V1, but again $ERROR
> does not allow the use of T. My code circumvents this now by using
> TIME in $ERROR and T in $DES, but I don't like the solution of
> defining everything twice.
> * Basically, my major issue is that I can use T in $DES, but any PK
> parameter I calculate from this can then not be used in $PK or
> $ERROR, where I would actually need this. I am sure there must be
> a solution, but I cannot see it…
> * Additional problem: My code only allows for continuous volume
> decrease over the first hemodialysis session. Also, after dialysis
> it jumps directly back to the volume that I had before dialysis.
> What I would like to model instead would be a continuous drop in
> volume over dialysis, and then a reincrease to pre-dialysis levels
> over the next ~2h. You mentioned a linear rate after dialysis. How
> do you implement this? Any suggestions, preferably in NONMEM code?
>
> What I have right now:
> $SUBROUTINE ADVAN13 TOL=5
> $MODEL NCOMP=2
> COMP=(CENTRAL)
> COMP=(PERIPH)
> ; ----------------[ Structural Model ]----------------
> $PK
> TVVM=THETA(1)
> VM=TVVM*EXP(ETA(1))
> TVKM=THETA(2)
> KM=TVKM
> TVV1=THETA(3)
> VC=TVV1*EXP(ETA(2))
> TVQ=THETA(4)
> Q=TVQ
> TVV2=THETA(5)
> V2=TVV2
> TVCL=THETA(6)
> CL=TVCL
> TVVAC=THETA(7)
> V1ACC=TVVAC
> ; ----------------[ Error Model ]----------------
> $ERROR
> ;parameter to describe volume decrease over dialysis
> VEDD=V1ACC
> ;after dialysis end (3h) volume back to higher levels
> IF (TIME.GT.3) VEDD=0
>
> VD1=VC -VEDD*TIME ;I would like to use T, but get an error message if I do
>
> CE1=A(1)/VD1
> IPRED=CE1
> DEL=0
> IF (IPRED.EQ.0) DEL=0.01
> W=CE1
> IRES=DV-IPRED
> IWRES=IRES/(W+DEL)
> Y=CE1+CE1*ERR(1)
> ;----------------[differential equations]-------------
> $DES
> VADD=V1ACC
> IF (T.GT.3) VADD=0
> V1=VC-VADD*T
> ;Scaling needed to be shifted from $PK as it uses V1
> S1=V1
> K12=Q/V1
> K21=Q/V2
> K10=CL/V1
> DADT(1) = - K12*A(1) + K21*A(2) - A(1)*VM/(KM+A(1)) -K10*A(1)
> DADT(2) = K12*A(1) - K21*A(2)
> Thanks again for your help. It is very much appreciated!
> Best
> Nele
> ______________________________________________________________
> Dr. Nele Käßner
> Principal Scientist Modeling and Simulation
> Global Pharmacometrics
> Experimental Medicine
> Takeda Pharmaceuticals International GmbH
> Thurgauerstrasse 130
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
> Visitor address:
> Alpenstrasse 3
> 8152 Glattpark-Opfikon (Zürich)
> Switzerland
> Phone: (+41) 44 / 55 51 404
> Mobile: (+41) 79 / 654 33 99
> mailto: [email protected]
> http://www.takeda.com
> -----Original Message-----
> From: James G Wright [mailto:[email protected]]
> Sent: Freitag, 18. Januar 2013 5:10
> To: Kaessner, Nele
> Cc: Ahmed N Mohamed; [email protected]
>
> Subject: Re: [NMusers] how to model blood volume change during and after hemodialysis?
>
> Dear Nele,
> You can use T if you just re-write the model using $DES and ADVAN13.
> What is slightly unusual and quite nice about dialysis volume changes is
> that you can model them with just one additional parameter. This
> fortunate situation arises because you know the times of dialysis
> (hopefully precisely). In-between dialysis occasions the plasma volume
> rises, as most subjects must/will consume more water than they can
> excrete, and then plasma volume falls back to the baseline during
> dialysis. So all you need to do is define you central volume as V1
> (usually immediately post-dialysis) and then an additional parameter
> V1acc which is the impact of V1 on the additional accumulation of fluid
> per day since the last dialysis, so it has units of L/day, and multiply
> by the time since the last dialysis finished. Provided dialysis is
> completed, you can generally assume that all of V1acc*days is removed at
> an approximately linear rate during dialysis. This model can account
> for differences in dialysis schedule (e.g. weekends) and you can put a
> random effect on V1acc to account for differences in fluid accumulation
> between different patients.
> It's not perfect, but it is simple. Usually, peripheral volumes are
> less sensitive to body water so you don't see anything on these. This
> simple model can often be successfully superimposed on a dialysis
> clearance model.
> Best regards, James
> On 18/01/2013 15:12, Kaessner, Nele wrote:
> > Dear Ahmed and all,
> >
> > First of all, thank you for your response.
>
> > The reason I believe that blood volume is altered is because I see an increase in concentrations until the end of hemodialysis, despite the fact that compound infusion ended two hours earlier. I would want to estimate the decreasing volume using information from both subjects with and without hemodialysis (for those without dialysis, concentrations drop as expected after the end of the infusion). Clearance via hemodialysis is not a problem by the way, compound is too big :-) > My problem mostly relates to the coding in NONMEM. How do I model a continuous change in V1 over time? $PK does not allow the variable 'T' to be used, and I don't just want to use TIME, as this would only consider time points actually contained in the data set.
>
> > Any suggestions?
> >
> > Thank you and best regards
> > Nele
> > ______________________________________________________________
> >
> > Dr. Nele Käßner
> > Principal Scientist Modeling and Simulation
> > Global Pharmacometrics
> > Experimental Medicine
> >
> > Takeda Pharmaceuticals International GmbH
> > Thurgauerstrasse 130
> > 8152 Glattpark-Opfikon (Zürich)
> > Switzerland
> >
> > Visitor address:
> > Alpenstrasse 3
> > 8152 Glattpark-Opfikon (Zürich)
> > Switzerland
> >
> > Phone: (+41) 44 / 55 51 404
> > Mobile: (+41) 79 / 654 33 99
> >
> > mailto: [email protected]
> > http://www.takeda.com
> >
> >
> > -----Original Message-----
> > From: Ahmed N Mohamed [mailto:[email protected]]
> > Sent: Freitag, 18. Januar 2013 3:28
> > To: Kaessner, Nele
> > Cc: [email protected]
>
> > Subject: Re: [NMusers] how to model blood volume change during and after hemodialysis?
>
> >
> > Hello,
> >
>
> > In terms of how long it takes to restore blood volume, i think it should be immediate because they usually give fluids during the dialysis to replace lost blood volume. Otherwise, there will be a significant drop in BP. You may have the volumes of fluid given in the patient charts if you have that.
>
> >
> > In terms of changing volume you can do that in two ways:
>
> > 1. If you have serial measurements of patient body weight, you can link that to volume as a covariate and it will change with change in weight (time-varying covariate). But this needs hourly or even more frequent weight measurements.
>
> >
>
> > 2. You can model the change in volume with time using a simple linear slope model where volume decreases with time during dialysis and increases with time after dialysis and estimate the slope for each process. However, i think this will be difficult to estimate separate from changes in clearance and the slope estimates you get will just be arbitrary. If you have samples from dialysate, it might be better.
>
> >
> > I hope this helps.
> >
> > ----- Original Message -----
> > From: "Nele Kaessner" <[email protected]>
> > To: [email protected]
> > Sent: Friday, January 18, 2013 8:24:05 AM
>
> > Subject: [NMusers] how to model blood volume change during and after hemodialysis?
>
> >
> >
> >
> >
> > Dear nmusers,
> >
> >
> >
>
> > I would like to model PK profiles of a compounds which mostly distributes in blood volume. The subjects which were investigated underwent hemodialysis for approx. the first three hours after infusion start, and the compound was given over a time period of ~5-10 min.
>
> >
>
> > It is well known that during hemodialysis, blood volume changes. Therefore, I would like to add a dynamic component to the central volume parameter, allowing it to decrease during hemodialysis and then to reincrease after dialysis has ended. I have all information about start and end time of both dosing and dialysis. Individual times between subjects differed. Unfortunately, I have not been creative enough to come up with a NONMEM code that can do this. Could any of you help out?
>
> >
>
> > Also, I probably do not have late enough time points to estimate when exactly blood volume would be restored. Does anyone know how much time the body needs after dialysis has ended until it is back to the original blood volume?
>
> >
> >
> >
> > Thanks for your help and best
> >
> > Nele
> >
> > ______________________________________________________________
> >
> >
> >
> > Dr. Nele Käßner
> >
> > Principal Scientist Modeling and Simulation
> >
> > Global Pharmacometrics
> >
> > Experimental Medicine
> >
> >
> >
> > Takeda Pharmaceuticals International GmbH
> >
> > Thurgauerstrasse 130
> >
> > 8152 Glattpark-Opfikon (Zürich)
> >
> > Switzerland
> >
> >
> >
> > Visitor address:
> >
> > Alpenstrasse 3
> >
> > 8152 Glattpark-Opfikon (Zürich)
> >
> > Switzerland
> >
> >
> >
> > Phone: (+41) 44 / 55 51 404
> >
> > Mobile: (+41) 79 / 654 33 99
> >
> >
> >
> > mailto: [email protected]
> >
> > http://www.takeda.com
> >
> > --------------------------------------------------------------------
> >
>
> > The content of this email and of any files transmitted may contain confidential, proprietary or legally privileged information and is intended solely for the use of the person/s or entity/ies to whom it is addressed. If you have received this email in error you have no permission whatsoever to use, copy, disclose or forward all or any of its contents. Please immediately notify the sender and thereafter delete this email and any attachments.
>
> >
> > --------------------------------------------------------------------
> >
> > --------------------------------------------------------------------
> >
>
> > The content of this email and of any files transmitted may contain confidential, proprietary or legally privileged information and is intended solely for the use of the person/s or entity/ies to whom it is addressed. If you have received this email in error you have no permission whatsoever to use, copy, disclose or forward all or any of its contents. Please immediately notify the sender and thereafter delete this email and any attachments.
>
> >
> > --------------------------------------------------------------------
> >
> --
> James G Wright PhD,
> Scientist, Wright Dose Ltd
> Tel: UK (0)772 5636914
> --------------------------------------------------------------------
>
> The content of this email and of any files transmitted may contain
> confidential, proprietary or legally privileged information and is intended
> solely for the use of the person/s or entity/ies to whom it is addressed. If
> you have received this email in error you have no permission whatsoever to use,
> copy, disclose or forward all or any of its contents. Please immediately notify
> the sender and thereafter delete this email and any attachments.
>
> --------------------------------------------------------------------
--
James G Wright PhD,
Scientist, Wright Dose Ltd
Tel: UK (0)772 5636914
Nele,
To set up the dataset for this type of problem, I would recommend inserting 'other type' records at the start and stop time of dialysis (evid=2). I would also include an indicator variable (I'll call it DIAL) to show when dialysis is on (DIAL=1) and off (DIAL=0). As James mentioned, NONMEM imputes covariate values backwards. This means as NONMEM works from TIME=N to TIME=N+1 it uses the values of the covariates on the TIME=N+1 record.
Example 1 Dataset: Not using EVID=2 records
ID TIME EVID DIAL
1 0 1 1 ;dose record and dialysis started
1 0.2 0 1 ;observation record
1 1 0 1 ;observation record
1 3 0 0 ;observation record and dialysis stop time
1 8 0 0 ;observation record
1 12 1 1 ;2nd dose record and dialysis started
1 14 0 1 ;observation record
1 18 0 0 ;observation record
For example 2,
dial=1 (on) as NONMEM steps from TIME=0 to TIME=0.2, 0.2 to 1
dial=0 (off) as NONMEM steps from TIME=1 to 3, and 3 to 8
dial=1 (on) as NONMEM steps from TIME=8 to 12 and 12 to 14
dial=0 (off) as NONMEM steps from TIME=14 to 18
Note: This leads to incorrect settings of dialysis.
Dialysis should not be shut off until time=3. However, the above dataset in effect shuts it off at TIME=1 and it remains off for 1 <= T <= 8. Dialysis should turn back on at time=12. However, the above dataset in effect turns dialysis on at TIME=8 and it remains on for 8 <= T <= 14. Dialysis should shut off at time=15. However, the above dataset in effect turns off dialysis at TIME=14 and it remains off for 14 <= T <= 18.
Example 2 Dataset: Using EVID=2 Records (Correct Behavior)
ID TIME EVID DIAL
1 0 1 0 ;dose record
1 0.01 2 1 ;dialysis started at time of dose (seconds after prior
record)
1 0.2 0 1 ;observation record
1 1 0 1 ;observation record
1 3 0 1 ;observation record
1 3.01 2 0 ;dialysis stop time (seconds after prior record)
1 8 0 0 ;observation record
1 12 1 0 ;2nd dose record
1 12.01 2 1 ;dialysis started for 2nd dose (seconds after prior record)
1 14 0 1 ;observation record
1 15 2 1 ;other type record to transition Vc from decr. to incr.
correctly
1 15.01 2 0 ;2nd dialysis stop time
1 18 0 0 ;observation
For example 1,
dial=0 (off) as NONMEM steps from TIME=0 to TIME=0.01
dial=1 (on) as NONMEM steps from TIME=0.01 to 0.2, 0.2 to 1, and 1 to 3
dial=0 (off) as NONMEM steps from TIME=3 to 3.01, 3.01 to 8, and 8 to 12
dial=1 (on) as NONMEM steps from TIME=12 to 12.01, 12.01 to 14, and 14 to 15
dial=0 (off) as NONMEM steps from TIME=15 to 15.01, etc.
Putting in an EVID=2 record for each dialysis start and stop time within seconds after the prior dose or observation record allows NONMEM to use the correct value of DIAL for T values in between the observations. If a dialysis start or stop time does not have a dose or observation record that could be within seconds prior to the dialysis record, insert an EVID=2 record (see TIME=15 in example. If it had not been included in the dataset NONMEM would have shut off dialysis at TIME=14).
I've modified the code you provided to fully implement the model based upon the dataset structure provided in Example 2. I have not tested the code so there may be typos or some other error that I may have missed.
Also note this code will not work if you use ADDL on dose records unless you always include an EVID=2 record immediately prior to the dialysis evid=2 records.
$SUBROUTINE ADVAN13 TOL=5
$MODEL NCOMP=2
COMP=(CENTRAL)
COMP=(PERIPH)
; ----------------[ Structural Model ]----------------
$PK
TVVM=THETA(1)
VM=TVVM*EXP(ETA(1))
TVKM=THETA(2)
KM=TVKM
;set initial value of Vc
TVV1=THETA(3)
INITVC=TVV1*EXP(ETA(2))
;slope of Vc during dialysis
VSLOPE=THETA(7) ;note equation implements the negative
;so initial estimate should be positive
;slope of Vc post-dialysis
;you could make this the same as VSLOPE but if you do the "Vc"
;will keep getting larger over time
;because the time dialysis is off is longer than the time
;dialysis is on.
VSLOPEUP=THETA(8)
TVQ=THETA(4)
Q=TVQ
TVV2=THETA(5)
V2=TVV2
TVCL=THETA(6)
CL=TVCL
S1=1 ;scaling will be taken care of in ERROR block
;----------------[differential equations]-------------
;NOTE: If you have an observation at the exact TIME of dialysis start or stop
; an infinite value of the objective function will occur because using
; linear functions forms a cusp at TIME=DSTART or DSTOP
; If you have an observation or dose at the exact time of a dialysis start
or stop
; increase the start or stop time of dialysis by a few seconds.
$DES
;initialize variables
IF(T.EQ.0) THEN
LASTINT=0
PREVINT=0
DSTART=0
DSTOP=0
ENDIF
;with the EVID=2 records in the data at each start & stop time of dialysis
;the following code will allow the computation of elapsed time within each
dialysis period
;PREVINT is set equal to the value of V1 calculated using the last value of T
NONMEM used prior
;to the EVID=2 dialysis record. This value of PREVINT will remain fixed until
the next EVID=2 record
; The - VSLOPEUP*(TLAST-DSTART) and + VSLOPE*(TLAST-DSTOP) in the PREVINT
equations is to correct
; the previous value of V1 to the current value of T because when the diff eq.
solver is stepping
; from TIME(N) to TIME(N+1) it may use a value of T slightly larger than
TIME(N+1).
; If you have questions about this aspect of the code, feel free to call me
(716-633-3463 ext. 236).
IF(EVID.EQ.2.AND.DIAL.EQ.1.AND.TYPE.EQ.1)THEN
DSTART=T
;capture the last value of V1 prior to turning dialysis on
PREVINT=LASTINT - VSLOPEUP*(TLAST-DSTART)
ENDIF
IF(EVID.EQ.2.AND.DIAL.EQ.0.AND.TYPE.EQ.1) THEN
DSTOP=T
;capture the last value of V1 prior to turning dialysis off
PREVINT=LASTINT + VSLOPE*(TLAST-DSTOP)
ENDIF
;if it is not the first dialysis start time set flg=1
FLG=0
IF(DSTART.GT.1)FLG=1
;first start Vc begins declining from the initial value of Vc
;2nd and greater start Vc begins declining from the value it had just prior to
re-starting dialysis
;the value of LASTINT will update every time NONMEM increments T
IF(DIAL.EQ.1) THEN
V1=(1-FLG)*(INITVC-VSLOPE*(T-DSTART)) + FLG*(PREVINT - VSLOPE*(T-DSTART))
LASTINT=V1
TLAST=T
ELSE
;when dialysis shuts off it should always start increasing from the value it had just prior to ;shutoff of dialysis
V1=PREVINT + VSLOPEUP*(T-DSTOP)
LASTINT=V1
TLAST=T
ENDIF
CP=A(1)/V1
K12=Q/V1
K21=Q/V2
K10=CL/V1
DADT(1) = - K12*A(1) + K21*A(2) - A(1)*VM/(KM+A(1)) -K10*A(1)
DADT(2) = K12*A(1) - K21*A(2)
; ----------------[ Error Model ]----------------
$ERROR
;Suggestion
;First model run: use DEL=0 & IF(AMT.GT.0)DEL=0.01 (only change W on dose
records)
;changing the ipred or w on a dose record does not change the MVOF
;Changing the W on observation records changes the MVOF
;Only if you get an IPRED=0 on an observation record should you implement
this coding
;because the MVOF is very sensitive to the value of DEL chosen.
;if a covariate or change in parameter values allows IPRED to be
0.00000001 for one model
;instead of 0 for the first model then that observation now has a weight
of 0.00000001 instead
;of 0.01. This can lead to large changes in the MVOF (>50) indicating
significance when the
;model only changed the estimate of the one observation by a very tiny
amount.
;If you have to implement this type of code on observation records, I
suggest running the same
;model with smaller and smaller values of DEL until the
;MVOF stays the same to prevent this issue. (I would start at DEL=0.00001)
IPRED=CP ;or IPRED=A(2)/V1
DEL=0
IF (IPRED.EQ.0) DEL=0.01
W=CP+DEL
IRES=DV-IPRED
IWRES=IRES/W
Y=IPRED + W*ERR(1)
I hope this is helpful to solving some of the problems that you have
encountered.
Luann Phillips
Director PK/PD
Cognigen Corporation
(716) 633-3463 ext. 236
Quoted reply history
On 1/21/2013 8:31 AM, James G Wright wrote:
> Dear Nele,
>
> You are on the right track, it is just the NONMEM coding you need to work out.
> Unfortunately, I have
> a lot of work on this week so I won't have time to go through this, but it is
> very likely you will
> get excellent answers from other people on the list.
>
> The only tip I would give is it is usually easier to code the dialysis as a
> covariate in the dataset
> than manually put the times in the code. Watch out though as NONMEM usually
> backward imputes
> covariates (so you set your dialysis covariate to 0 at the start of dialysis
> and 1 at the end to get
> the correct profile).
>
> Good luck with the idiosyncracies of NONMEM! Kind regards, James
>
> On 21/01/2013 09:21, Kaessner, Nele wrote:
>
> > Hi James, dear all,
> > Thanks for your answer. I have understood what you were writing, however I
> > still have problems to
> > implement the suggestions in NONMEM. This is mainly due to the somewhat
> > inflexible way NONMEM
> > works. My problems are the following:
> >
> > * The final V1 needs to be defined in $DES, as otherwise I cannot use T
> > * V1 is used as a scaling factor to determine concentration. This would
> > normally be done in $PK,
> > where I cannot use parameters that are defined in $DES
> > * Y and IPRED are calculated using A(1) and V1, but again $ERROR does not
> > allow the use of T. My
> > code circumvents this now by using TIME in $ERROR and T in $DES, but I
> > don't like the solution
> > of defining everything twice.
> > * Basically, my major issue is that I can use T in $DES, but any PK parameter
> > I calculate from
> > this can then not be used in $PK or $ERROR, where I would actually need
> > this. I am sure there
> > must be a solution, but I cannot see it…
> > * Additional problem: My code only allows for continuous volume decrease over
> > the first
> > hemodialysis session. Also, after dialysis it jumps directly back to the
> > volume that I had
> > before dialysis. What I would like to model instead would be a continuous
> > drop in volume over
> > dialysis, and then a reincrease to pre-dialysis levels over the next ~2h.
> > You mentioned a
> > linear rate after dialysis. How do you implement this? Any suggestions,
> > preferably in NONMEM code?
> >
> > What I have right now:
> > $SUBROUTINE ADVAN13 TOL=5
> > $MODEL NCOMP=2
> > COMP=(CENTRAL)
> > COMP=(PERIPH)
> > ; ----------------[ Structural Model ]----------------
> > $PK
> > TVVM=THETA(1)
> > VM=TVVM*EXP(ETA(1))
> > TVKM=THETA(2)
> > KM=TVKM
> > TVV1=THETA(3)
> > VC=TVV1*EXP(ETA(2))
> > TVQ=THETA(4)
> > Q=TVQ
> > TVV2=THETA(5)
> > V2=TVV2
> > TVCL=THETA(6)
> > CL=TVCL
> > TVVAC=THETA(7)
> > V1ACC=TVVAC
> > ; ----------------[ Error Model ]----------------
> > $ERROR
> > ;parameter to describe volume decrease over dialysis
> > VEDD=V1ACC
> > ;after dialysis end (3h) volume back to higher levels
> > IF (TIME.GT.3) VEDD=0
> > VD1=VC -VEDD*TIME ;I would like to use T, but get an error message if I do
> > CE1=A(1)/VD1
> > IPRED=CE1
> > DEL=0
> > IF (IPRED.EQ.0) DEL=0.01
> > W=CE1
> > IRES=DV-IPRED
> > IWRES=IRES/(W+DEL)
> > Y=CE1+CE1*ERR(1)
> > ;----------------[differential equations]-------------
> > $DES
> > VADD=V1ACC
> > IF (T.GT.3) VADD=0
> > V1=VC-VADD*T
> > ;Scaling needed to be shifted from $PK as it uses V1
> > S1=V1
> > K12=Q/V1
> > K21=Q/V2
> > K10=CL/V1
> > DADT(1) = - K12*A(1) + K21*A(2) - A(1)*VM/(KM+A(1)) -K10*A(1)
> > DADT(2) = K12*A(1) - K21*A(2)
> > Thanks again for your help. It is very much appreciated!
> > Best
> > Nele
> > ______________________________________________________________
> > Dr. Nele Käßner
> > Principal Scientist Modeling and Simulation
> > Global Pharmacometrics
> > Experimental Medicine
> > Takeda Pharmaceuticals International GmbH
> > Thurgauerstrasse 130
> > 8152 Glattpark-Opfikon (Zürich)
> > Switzerland
> > Visitor address:
> > Alpenstrasse 3
> > 8152 Glattpark-Opfikon (Zürich)
> > Switzerland
> > Phone: (+41) 44 / 55 51 404
> > Mobile: (+41) 79 / 654 33 99
> > mailto: [email protected]
> > http://www.takeda.com
> > -----Original Message-----
> > From: James G Wright [mailto:[email protected]]
> > Sent: Freitag, 18. Januar 2013 5:10
> > To: Kaessner, Nele
> > Cc: Ahmed N Mohamed; [email protected]
> > Subject: Re: [NMusers] how to model blood volume change during and after
> > hemodialysis?
> > Dear Nele,
> > You can use T if you just re-write the model using $DES and ADVAN13.
> > What is slightly unusual and quite nice about dialysis volume changes is
> > that you can model them with just one additional parameter. This
> > fortunate situation arises because you know the times of dialysis
> > (hopefully precisely). In-between dialysis occasions the plasma volume
> > rises, as most subjects must/will consume more water than they can
> > excrete, and then plasma volume falls back to the baseline during
> > dialysis. So all you need to do is define you central volume as V1
> > (usually immediately post-dialysis) and then an additional parameter
> > V1acc which is the impact of V1 on the additional accumulation of fluid
> > per day since the last dialysis, so it has units of L/day, and multiply
> > by the time since the last dialysis finished. Provided dialysis is
> > completed, you can generally assume that all of V1acc*days is removed at
> > an approximately linear rate during dialysis. This model can account
> > for differences in dialysis schedule (e.g. weekends) and you can put a
> > random effect on V1acc to account for differences in fluid accumulation
> > between different patients.
> > It's not perfect, but it is simple. Usually, peripheral volumes are
> > less sensitive to body water so you don't see anything on these. This
> > simple model can often be successfully superimposed on a dialysis
> > clearance model.
> > Best regards, James
> > On 18/01/2013 15:12, Kaessner, Nele wrote:
> > > Dear Ahmed and all,
> > >
> > > First of all, thank you for your response.
> > > The reason I believe that blood volume is altered is because I see an
> > increase in concentrations
> > until the end of hemodialysis, despite the fact that compound infusion ended
> > two hours earlier. I
> > would want to estimate the decreasing volume using information from both
> > subjects with and without
> > hemodialysis (for those without dialysis, concentrations drop as expected after
> > the end of the
> > infusion). Clearance via hemodialysis is not a problem by the way, compound is
> > too big :-)
> > > My problem mostly relates to the coding in NONMEM. How do I model a
> > continuous change in V1 over
> > time? $PK does not allow the variable 'T' to be used, and I don't just want to
> > use TIME, as this
> > would only consider time points actually contained in the data set.
> > > Any suggestions?
> > >
> > > Thank you and best regards
> > > Nele
> > > ______________________________________________________________
> > >
> > > Dr. Nele Käßner
> > > Principal Scientist Modeling and Simulation
> > > Global Pharmacometrics
> > > Experimental Medicine
> > >
> > > Takeda Pharmaceuticals International GmbH
> > > Thurgauerstrasse 130
> > > 8152 Glattpark-Opfikon (Zürich)
> > > Switzerland
> > >
> > > Visitor address:
> > > Alpenstrasse 3
> > > 8152 Glattpark-Opfikon (Zürich)
> > > Switzerland
> > >
> > > Phone: (+41) 44 / 55 51 404
> > > Mobile: (+41) 79 / 654 33 99
> > >
> > > mailto: [email protected]
> > > http://www.takeda.com
> > >
> > >
> > > -----Original Message-----
> > > From: Ahmed N Mohamed [mailto:[email protected]]
> > > Sent: Freitag, 18. Januar 2013 3:28
> > > To: Kaessner, Nele
> > > Cc: [email protected]
> > > Subject: Re: [NMusers] how to model blood volume change during and after
> > hemodialysis?
> > >
> > > Hello,
> > >
> > > In terms of how long it takes to restore blood volume, i think it should be
> > immediate because
> > they usually give fluids during the dialysis to replace lost blood volume.
> > Otherwise, there will
> > be a significant drop in BP. You may have the volumes of fluid given in the
> > patient charts if you
> > have that.
> > >
> > > In terms of changing volume you can do that in two ways:
> > > 1. If you have serial measurements of patient body weight, you can link that
> > to volume as a
> > covariate and it will change with change in weight (time-varying covariate).
> > But this needs hourly
> > or even more frequent weight measurements.
> > >
> > > 2. You can model the change in volume with time using a simple linear slope
> > model where volume
> > decreases with time during dialysis and increases with time after dialysis and
> > estimate the slope
> > for each process. However, i think this will be difficult to estimate separate
> > from changes in
> > clearance and the slope estimates you get will just be arbitrary. If you have
> > samples from
> > dialysate, it might be better.
> > >
> > > I hope this helps.
> > >
> > > ----- Original Message -----
> > > From: "Nele Kaessner" <[email protected]>
> > > To: [email protected]
> > > Sent: Friday, January 18, 2013 8:24:05 AM
> > > Subject: [NMusers] how to model blood volume change during and after
> > hemodialysis?
> > >
> > >
> > >
> > >
> > > Dear nmusers,
> > >
> > >
> > >
> > > I would like to model PK profiles of a compounds which mostly distributes in
> > blood volume. The
> > subjects which were investigated underwent hemodialysis for approx. the first
> > three hours after
> > infusion start, and the compound was given over a time period of ~5-10 min.
> > >
> > > It is well known that during hemodialysis, blood volume changes. Therefore, I
> > would like to add
> > a dynamic component to the central volume parameter, allowing it to decrease
> > during hemodialysis
> > and then to reincrease after dialysis has ended. I have all information about
> > start and end time
> > of both dosing and dialysis. Individual times between subjects differed.
> > Unfortunately, I have not
> > been creative enough to come up with a NONMEM code that can do this. Could any
> > of you help out?
> > >
> > > Also, I probably do not have late enough time points to estimate when exactly
> > blood volume would
> > be restored. Does anyone know how much time the body needs after dialysis has
> > ended until it is
> > back to the original blood volume?
> > >
> > >
> > >
> > > Thanks for your help and best
> > >
> > > Nele
> > >
> > > ______________________________________________________________
> > >
> > >
> > >
> > > Dr. Nele Käßner
> > >
> > > Principal Scientist Modeling and Simulation
> > >
> > > Global Pharmacometrics
> > >
> > > Experimental Medicine
> > >
> > >
> > >
> > > Takeda Pharmaceuticals International GmbH
> > >
> > > Thurgauerstrasse 130
> > >
> > > 8152 Glattpark-Opfikon (Zürich)
> > >
> > > Switzerland
> > >
> > >
> > >
> > > Visitor address:
> > >
> > > Alpenstrasse 3
> > >
> > > 8152 Glattpark-Opfikon (Zürich)
> > >
> > > Switzerland
> > >
> > >
> > >
> > > Phone: (+41) 44 / 55 51 404
> > >
> > > Mobile: (+41) 79 / 654 33 99
> > >
> > >
> > >
> > > mailto: [email protected]
> > >
> > > http://www.takeda.com
> > >
> > > --------------------------------------------------------------------
> > >
> > > The content of this email and of any files transmitted may contain
> > confidential, proprietary or
> > legally privileged information and is intended solely for the use of the
> > person/s or entity/ies to
> > whom it is addressed. If you have received this email in error you have no
> > permission whatsoever
> > to use, copy, disclose or forward all or any of its contents. Please
> > immediately notify the sender
> > and thereafter delete this email and any attachments.
> > >
> > > --------------------------------------------------------------------
> > >
> > > --------------------------------------------------------------------
> > >
> > > The content of this email and of any files transmitted may contain
> > confidential, proprietary or
> > legally privileged information and is intended solely for the use of the
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> > immediately notify the sender
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> > > --------------------------------------------------------------------
> > >
> > --
> > James G Wright PhD,
> > Scientist, Wright Dose Ltd
> > Tel: UK (0)772 5636914
> > --------------------------------------------------------------------
> >
> > The content of this email and of any files transmitted may contain
> > confidential, proprietary or legally privileged information and is intended
> > solely for the use of the person/s or entity/ies to whom it is addressed. If
> > you have received this email in error you have no permission whatsoever to use,
> > copy, disclose or forward all or any of its contents. Please immediately notify
> > the sender and thereafter delete this email and any attachments.
> >
> > --------------------------------------------------------------------
>
> --
> James G Wright PhD,
> Scientist, Wright Dose Ltd
> Tel: UK (0)772 5636914