Greetings NMusers,
Does nonmem have the capacity, unbeknownst to me, for modeling two simultaneous
drugs?
I would like some suggestions about how to define the dataset and model for a
subcutaneous drug and oral drug being administered on different schedules. I
would use DVID = 1 and 2 for the two plasma pk observations. I figure this
soft of thing had to be dealt with in the past when trying to model dynamic
DDIs (vs, just taking one of the drugs as a covariate on the other's
parameters).
One approach is to specify the compartments for each to be dosed into then have
those feed the central, but I'm curious to see if there is something more
subtle in the nonmem syntax. Is there something about EVID, that I don't know
that would help (beyond EVID=1 for dosing)
What if you had two oral drugs? Would you treat the two dosing compartments as
separate and possibly link them together at the parameter/covariance level?
Thanks,
Chris
Chris Penland, PhD
ECD / Quantitative Clinical Pharmacology
Waltham, MA USA
________________________________
Confidentiality Notice: This message is private and may contain confidential
and proprietary information. If you have received this message in error, please
notify us and remove it from your system and note that you must not copy,
distribute or take any action in reliance on it. Any unauthorized use or
disclosure of the contents of this message is not permitted and may be unlawful.
Simultaneous pk model of 2 drugs
Hi Chris,
I think that the most straight-forward way to handle this is to have two sets
of compartments and write the $DES block manually (or writing the algebraic
equations if it's a one- or two-compartment model).
It wouldn't be straight-forward to model if the subjects receive the drugs at
the same time. If the drugs are received at separate times (like different
periods of a study or even different studies), then the DVID flag idea would
work, too.
There are only five EVID values as far as I know, and there's not a subtle way
to use them for two doses, I don't think:
• 0= observation
• 1= dose
• 2= other (I usually use it to reset the compartment)
• 3= reset the subject
• 4= reset and dose at the same time
Thanks,
Bill
Quoted reply history
> On Sep 2, 2016, at 1:22 PM, Penland, Chris <[email protected]>
> wrote:
>
> Greetings NMusers,
>
> Does nonmem have the capacity, unbeknownst to me, for modeling two
> simultaneous drugs?
>
> I would like some suggestions about how to define the dataset and model for a
> subcutaneous drug and oral drug being administered on different schedules. I
> would use DVID = 1 and 2 for the two plasma pk observations. I figure this
> soft of thing had to be dealt with in the past when trying to model dynamic
> DDIs (vs, just taking one of the drugs as a covariate on the other’s
> parameters).
>
> One approach is to specify the compartments for each to be dosed into then
> have those feed the central, but I’m curious to see if there is something
> more subtle in the nonmem syntax. Is there something about EVID, that I don’t
> know that would help (beyond EVID=1 for dosing)
>
> What if you had two oral drugs? Would you treat the two dosing compartments
> as separate and possibly link them together at the parameter/covariance level?
>
> Thanks,
> Chris
>
>
> Chris Penland, PhD
> ECD / Quantitative Clinical Pharmacology
> Waltham, MA USA
>
>
> Confidentiality Notice: This message is private and may contain confidential
> and proprietary information. If you have received this message in error,
> please notify us and remove it from your system and note that you must not
> copy, distribute or take any action in reliance on it. Any unauthorized use
> or disclosure of the contents of this message is not permitted and may be
> unlawful.
>
>
>
>
>
>
>
>
Chris,
If the elimination is first-order for both drugs then its probably computationally quicker to use ADVAN5 (or ADVAN7). This lets you specify separate compartments to account for the input, distribution and elimination of each drug.
The input dose is defined by the usual data items (AMT, RATE, II, ADDL, SS) with CMT linking the input to the compartment you define with ADVAN5 (or ADVAN7).
In my opinion a user defined DVID is more flexible and a clearer way of linking the DV with the model prediction. I use clearer to mean for a human reading the code to understand what is intended. CMT can work sometimes but won't work for things like effect predictions that are not amounts in a compartment.
I am nor sure what Bill means with EVID=2 and EVID=3. EVID=2 does not reset any compartment but it can be used to turn a compartment on or off. It is commonly used to define a record used for prediction in $TABLE at a time when there is no dose or observation event. EVID=3 resets all compartments. All EVIDs are subject specific.
Best wishes,
Nick
This is from the NONMEM online help. There are some minor additional features
with NONMEM 7 which you can find for yourself.
0 Observation event. The DV data item is an observation. The CMT
data item specifies which compartment is being observed. Dose-
related data items (AMT, RATE, II, ADDL, SS) must be zero.
1 Dose event. The CMT data item specifies which compartment is
being dosed. The DV data item is ignored. One or more of AMT,
RATE, II, ADDL, SS data items must be non-zero to define the
dose.
2 Other-type event. The DV data item is ignored. Dose-related
data items must be zero. Examples of other-type events are: A
compartment is turned on or off (CMT specifies which compartment
is to be turned on or off); a prediction is obtained at a speci-
fied time so that it may be displayed in a table or scatterplot
(PCMT specifies the compartment from which the prediction is
obtained); some event occurs at a different time than any obser- |
vation or dose event, e.g. a covariate such as weight changes, an |
intervention such as hemodialysis is started or stopped.
3 Reset event. The kinetic system is re-initialized. Time is
reset to the time of the event record, the amounts in each com-
partment are reset to zero, the on/off status of each compartment
is reset to its initial status. The DV data item is ignored.
Dose-related data items must be zero.
4 Reset-and-dose event. The system is first reset, and then a dose
is given. The DV data item is ignored.
Quoted reply history
On 03-Sep-16 07:01, William Denney wrote:
> Hi Chris,
>
> I think that the most straight-forward way to handle this is to have two sets of compartments and write the $DES block manually (or writing the algebraic equations if it's a one- or two-compartment model).
>
> It wouldn't be straight-forward to model if the subjects receive the drugs at the same time. If the drugs are received at separate times (like different periods of a study or even different studies), then the DVID flag idea would work, too.
>
> There are only five EVID values as far as I know, and there's not a subtle way to use them for two doses, I don't think:
>
> • 0= observation
> • 1= dose
> • 2= other (I usually use it to reset the compartment)
> • 3= reset the subject
> • 4= reset and dose at the same time
>
> Thanks,
>
> Bill
>
> On Sep 2, 2016, at 1:22 PM, Penland, Chris < [email protected] < mailto: [email protected] >> wrote:
>
> > Greetings NMusers,
> >
> > Does nonmem have the capacity, unbeknownst to me, for modeling two simultaneous drugs?
> >
> > I would like some suggestions about how to define the dataset and model for a subcutaneous drug and oral drug being administered on different schedules. I would use DVID = 1 and 2 for the two plasma pk observations. I figure this soft of thing had to be dealt with in the past when trying to model dynamic DDIs (vs, just taking one of the drugs as a covariate on the other’s parameters).
> >
> > One approach is to specify the compartments for each to be dosed into then have those feed the central, but I’m curious to see if there is something more subtle in the nonmem syntax. Is there something about EVID, that I don’t know that would help (beyond EVID=1 for dosing)
> >
> > What if you had two oral drugs? Would you treat the two dosing compartments as separate and possibly link them together at the parameter/covariance level?
> >
> > Thanks,
> >
> > Chris
> >
> > Chris Penland, PhD
> >
> > ECD / Quantitative Clinical Pharmacology
> >
> > Waltham, MA USA
> >
> > ------------------------------------------------------------------------
> >
> > *Confidentiality Notice: *This message is private and may contain confidential and proprietary information. If you have received this message in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this message is not permitted and may be unlawful.
--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72
email: [email protected]
http://holford.fmhs.auckland.ac.nz/
"Declarative languages are a form of dementia -- they have no memory of events"
Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop,
B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models
- tests of assumptions and predictions. Journal of Pharmacology & Clinical
Toxicology. 2014;2(2):1023-34.
Holford N. Clinical pharmacology = disease progression + drug action. Br J Clin
Pharmacol. 2015;79(1):18-27.
I think there is no difference between simultaneous administration or not as the dose is directed to the appropriate compartment using CMT variable. In any case two dosing records (one for each drug) are needed, and the relative times of these records are not important. So it is exactly like two models (one for each drug) written in one control stream (with different compartments used for each drug). CMT is used to direct the dose. DVID or CMT can be used to identify observations for each drug. Interactions can be studied using correlations of random effects, or using joint parameters, or directly specifying how concentration of one drug influences the parameters of the other drug.
Regards,
Leonid
Quoted reply history
On 9/2/2016 3:01 PM, William Denney wrote:
> Hi Chris,
>
> I think that the most straight-forward way to handle this is to have two
> sets of compartments and write the $DES block manually (or writing the
> algebraic equations if it's a one- or two-compartment model).
>
> It wouldn't be straight-forward to model if the subjects receive the
> drugs at the same time. If the drugs are received at separate times
> (like different periods of a study or even different studies), then the
> DVID flag idea would work, too.
>
> There are only five EVID values as far as I know, and there's not a
> subtle way to use them for two doses, I don't think:
>
> • 0= observation
> • 1= dose
> • 2= other (I usually use it to reset the compartment)
> • 3= reset the subject
> • 4= reset and dose at the same time
>
> Thanks,
>
> Bill
>
> On Sep 2, 2016, at 1:22 PM, Penland, Chris
> <[email protected] <mailto:[email protected]>>
> wrote:
>
> > Greetings NMusers,
> >
> > Does nonmem have the capacity, unbeknownst to me, for modeling two
> > simultaneous drugs?
> >
> > I would like some suggestions about how to define the dataset and
> > model for a subcutaneous drug and oral drug being administered on
> > different schedules. I would use DVID = 1 and 2 for the two plasma pk
> > observations. I figure this soft of thing had to be dealt with in the
> > past when trying to model dynamic DDIs (vs, just taking one of the
> > drugs as a covariate on the other’s parameters).
> >
> > One approach is to specify the compartments for each to be dosed into
> > then have those feed the central, but I’m curious to see if there is
> > something more subtle in the nonmem syntax. Is there something about
> > EVID, that I don’t know that would help (beyond EVID=1 for dosing)
> >
> > What if you had two oral drugs? Would you treat the two dosing
> > compartments as separate and possibly link them together at the
> > parameter/covariance level?
> >
> > Thanks,
> >
> > Chris
> >
> > Chris Penland, PhD
> >
> > ECD / Quantitative Clinical Pharmacology
> >
> > Waltham, MA USA
> >
> > ------------------------------------------------------------------------
> >
> > *Confidentiality Notice: *This message is private and may contain
> > confidential and proprietary information. If you have received this
> > message in error, please notify us and remove it from your system and
> > note that you must not copy, distribute or take any action in reliance
> > on it. Any unauthorized use or disclosure of the contents of this
> > message is not permitted and may be unlawful.
Hello Chris,
What is the point of modeling 2 drugs in one NONMEM
code? Do the drugs interact? For example, you can have 2 monoclonal
antibodies competing for or binding to the same target and/or concentration of
one drug changes elimination rate or some other parameters of the other
one. If they do not interact, you can
model them separately. In some cases,
even if they interact you can model them separately using dose of one drug as a
covariate for the other one.
Regards,
Pavel
Quoted reply history
On Fri, Sep 02, 2016 at 01:22 PM, Penland, Chris wrote:
Greetings NMusers,
Does nonmem have the capacity, unbeknownst to me, for modeling two simultaneous drugs?
I would like some suggestions about how to define the dataset and model for a subcutaneous drug and oral drug being administered on different schedules. I would use DVID = 1 and 2 for the two plasma pk observations. I figure this soft of thing had to be dealt with in the past when trying to model dynamic DDIs (vs, just taking one of the drugs as a covariate on the other’s parameters).
One approach is to specify the compartments for each to be dosed into then have those feed the central, but I’m curious to see if there is something more subtle in the nonmem syntax. Is there something about EVID, that I don’t know that
would help (beyond EVID=1 for dosing)
What if you had two oral drugs? Would you treat the two dosing compartments as separate and possibly link them together at the parameter/covariance level?
Thanks,
Chris
Chris Penland, PhD
ECD / Quantitative Clinical Pharmacology
Waltham, MA USA
Confidentiality Notice:
This message is private and may contain confidential and proprietary information. If you have received this message in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this message is not permitted and may be unlawful.
Hi all,
I guess that if both drugs are given to the same person, it makes a lot of sense to perform simultaneous modeling, because of physiology, a lot of parameters will show covariance. The PK of one drug can therefore partially explain the PK of the other one (and vice versa).
Cheers,
Rob
---
Dr. R. ter Heine, hospital pharmacist-clinical pharmacologist
Head of Clinical Trials Unit, Dept. of Pharmacy
Radboudumc
T +31-24-36 16405
F +31-24-36 68755
Quoted reply history
Van: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] Namens Pavel Belo
Verzonden: dinsdag 6 september 2016 3:04
Aan: Penland, Chris
CC: nmusers_at_globomaxnm.com
Onderwerp: RE: [NMusers] Simultaneous pk model of 2 drugs
Hello Chris,
What is the point of modeling 2 drugs in one NONMEM code? Do the drugs interact? For example, you can have 2 monoclonal antibodies competing for or binding to the same target and/or concentration of one drug changes elimination rate or some other parameters of the other one. If they do not interact, you can model them separately. In some cases, even if they interact you can model them separately using dose of one drug as a covariate for the other one.
Regards,
Pavel
On Fri, Sep 02, 2016 at 01:22 PM, Penland, Chris wrote:
Greetings NMusers,
Does nonmem have the capacity, unbeknownst to me, for modeling two simultaneous drugs?
I would like some suggestions about how to define the dataset and model for a subcutaneous drug and oral drug being administered on different schedules. I would use DVID = 1 and 2 for the two plasma pk observations. I figure this soft of thing had to be dealt with in the past when trying to model dynamic DDIs (vs, just taking one of the drugs as a covariate on the other’s parameters).
One approach is to specify the compartments for each to be dosed into then have those feed the central, but I’m curious to see if there is something more subtle in the nonmem syntax. Is there something about EVID, that I don’t know that would help (beyond EVID=1 for dosing)
What if you had two oral drugs? Would you treat the two dosing compartments as separate and possibly link them together at the parameter/covariance level?
Thanks,
Chris
Chris Penland, PhD
ECD / Quantitative Clinical Pharmacology
Waltham, MA USA
________________________________
Confidentiality Notice: This message is private and may contain confidential and proprietary information. If you have received this message in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this message is not permitted and may be unlawful.
Het Radboudumc staat geregistreerd bij de Kamer van Koophandel in het handelsregister onder nummer 41055629.
The Radboud university medical center is listed in the Commercial Register of the Chamber of Commerce under file number 41055629.
Hi all,
I guess that if both drugs are given to the same person, it makes a lot of
sense to perform simultaneous modeling, because of physiology, a lot of
parameters will show covariance. The PK of one drug can therefore partially
explain the PK of the other one (and vice versa).
Cheers,
Rob
---
Dr. R. ter Heine, hospital pharmacist-clinical pharmacologist
Head of Clinical Trials Unit, Dept. of Pharmacy
Radboudumc
T +31-24-36 16405
F +31-24-36 68755
Quoted reply history
Van: [email protected] [mailto:[email protected]] Namens
Pavel Belo
Verzonden: dinsdag 6 september 2016 3:04
Aan: Penland, Chris
CC: [email protected]
Onderwerp: RE: [NMusers] Simultaneous pk model of 2 drugs
Hello Chris,
What is the point of modeling 2 drugs in one NONMEM code? Do the drugs
interact? For example, you can have 2 monoclonal antibodies competing for or
binding to the same target and/or concentration of one drug changes elimination
rate or some other parameters of the other one. If they do not interact, you
can model them separately. In some cases, even if they interact you can model
them separately using dose of one drug as a covariate for the other one.
Regards,
Pavel
On Fri, Sep 02, 2016 at 01:22 PM, Penland, Chris wrote:
Greetings NMusers,
Does nonmem have the capacity, unbeknownst to me, for modeling two simultaneous
drugs?
I would like some suggestions about how to define the dataset and model for a
subcutaneous drug and oral drug being administered on different schedules. I
would use DVID = 1 and 2 for the two plasma pk observations. I figure this
soft of thing had to be dealt with in the past when trying to model dynamic
DDIs (vs, just taking one of the drugs as a covariate on the other’s
parameters).
One approach is to specify the compartments for each to be dosed into then have
those feed the central, but I’m curious to see if there is something more
subtle in the nonmem syntax. Is there something about EVID, that I don’t know
that would help (beyond EVID=1 for dosing)
What if you had two oral drugs? Would you treat the two dosing compartments as
separate and possibly link them together at the parameter/covariance level?
Thanks,
Chris
Chris Penland, PhD
ECD / Quantitative Clinical Pharmacology
Waltham, MA USA
________________________________
Confidentiality Notice: This message is private and may contain confidential
and proprietary information. If you have received this message in error, please
notify us and remove it from your system and note that you must not copy,
distribute or take any action in reliance on it. Any unauthorized use or
disclosure of the contents of this message is not permitted and may be unlawful.
Het Radboudumc staat geregistreerd bij de Kamer van Koophandel in het
handelsregister onder nummer 41055629.
The Radboud university medical center is listed in the Commercial Register of
the Chamber of Commerce under file number 41055629.
Thanks to many who have responded –
To Pavel and Rob, yes the goal is to simultaneously model the two drugs (one
peptide, one small molecule) – the interaction is putatively through a dynamic
effect of one drug on renal function that one is partially dependent on and the
other is highly dependent on. Both are active against the same PD marker.
Regards to all
-chris
Quoted reply history
From: [email protected] [mailto:[email protected]]
Sent: Tuesday, September 06, 2016 7:35 AM
To: [email protected]; Penland, Chris
Cc: [email protected]
Subject: RE: [NMusers] Simultaneous pk model of 2 drugs
Hi all,
I guess that if both drugs are given to the same person, it makes a lot of
sense to perform simultaneous modeling, because of physiology, a lot of
parameters will show covariance. The PK of one drug can therefore partially
explain the PK of the other one (and vice versa).
Cheers,
Rob
---
Dr. R. ter Heine, hospital pharmacist-clinical pharmacologist
Head of Clinical Trials Unit, Dept. of Pharmacy
Radboudumc
T +31-24-36 16405
F +31-24-36 68755
Van: [email protected]<mailto:[email protected]>
[mailto:[email protected]] Namens Pavel Belo
Verzonden: dinsdag 6 september 2016 3:04
Aan: Penland, Chris
CC: [email protected]<mailto:[email protected]>
Onderwerp: RE: [NMusers] Simultaneous pk model of 2 drugs
Hello Chris,
What is the point of modeling 2 drugs in one NONMEM code? Do the drugs
interact? For example, you can have 2 monoclonal antibodies competing for or
binding to the same target and/or concentration of one drug changes elimination
rate or some other parameters of the other one. If they do not interact, you
can model them separately. In some cases, even if they interact you can model
them separately using dose of one drug as a covariate for the other one.
Regards,
Pavel
On Fri, Sep 02, 2016 at 01:22 PM, Penland, Chris wrote:
Greetings NMusers,
Does nonmem have the capacity, unbeknownst to me, for modeling two simultaneous
drugs?
I would like some suggestions about how to define the dataset and model for a
subcutaneous drug and oral drug being administered on different schedules. I
would use DVID = 1 and 2 for the two plasma pk observations. I figure this
soft of thing had to be dealt with in the past when trying to model dynamic
DDIs (vs, just taking one of the drugs as a covariate on the other’s
parameters).
One approach is to specify the compartments for each to be dosed into then have
those feed the central, but I’m curious to see if there is something more
subtle in the nonmem syntax. Is there something about EVID, that I don’t know
that would help (beyond EVID=1 for dosing)
What if you had two oral drugs? Would you treat the two dosing compartments as
separate and possibly link them together at the parameter/covariance level?
Thanks,
Chris
Chris Penland, PhD
ECD / Quantitative Clinical Pharmacology
Waltham, MA USA
________________________________
Confidentiality Notice: This message is private and may contain confidential
and proprietary information. If you have received this message in error, please
notify us and remove it from your system and note that you must not copy,
distribute or take any action in reliance on it. Any unauthorized use or
disclosure of the contents of this message is not permitted and may be unlawful.
Het Radboudumc staat geregistreerd bij de Kamer van Koophandel in het
handelsregister onder nummer 41055629.
The Radboud university medical center is listed in the Commercial Register of
the Chamber of Commerce under file number 41055629.
________________________________
Confidentiality Notice: This message is private and may contain confidential
and proprietary information. If you have received this message in error, please
notify us and remove it from your system and note that you must not copy,
distribute or take any action in reliance on it. Any unauthorized use or
disclosure of the contents of this message is not permitted and may be unlawful.
Hi all,
I don't think we should do analyze two drugs simultaneously. I DO agree that two drugs may correlate to each other through physiology.
However I think we should analyze factors in physiology first. Then we can analyze the correlation between two drug.
Regards,
Masaki
Quoted reply history
On 2016/09/06 20:34, [email protected] wrote:
> Hi all,
>
> I guess that if both drugs are given to the same person, it makes a lot of sense to perform simultaneous modeling, because of physiology, a lot of parameters will show covariance. The PK of one drug can therefore partially explain the PK of the other one (and vice versa).
>
> Cheers,
>
> Rob
>
> **
>
> *---*
>
> *Dr. R. ter Heine, hospital pharmacist-clinical pharmacologist*
>
> *Head of Clinical Trials Unit, Dept. of Pharmacy*
>
> *Radboudumc *
>
> T +31-24-36 16405
>
> F +31-24-36 68755
>
> *Van:* [email protected] [ mailto: [email protected] ] *Namens *Pavel Belo
>
> *Verzonden:* dinsdag 6 september 2016 3:04
> *Aan:* Penland, Chris
> *CC:* [email protected]
> *Onderwerp:* RE: [NMusers] Simultaneous pk model of 2 drugs
>
> Hello Chris,
>
> What is the point of modeling 2 drugs in one NONMEM code? Do the drugs interact? For example, you can have 2 monoclonal antibodies competing for or binding to the same target and/or concentration of one drug changes elimination rate or some other parameters of the other one. If they do not interact, you can model them separately. In some cases, even if they interact you can model them separately using dose of one drug as a covariate for the other one.
>
> Regards,
>
> Pavel
>
> On Fri, Sep 02, 2016 at 01:22 PM, Penland, Chris wrote:
>
> Greetings NMusers,
>
> Does nonmem have the capacity, unbeknownst to me, for modeling two
> simultaneous drugs?
>
> I would like some suggestions about how to define the dataset and
> model for a subcutaneous drug and oral drug being administered on
> different schedules. I would use DVID = 1 and 2 for the two plasma
> pk observations. I figure this soft of thing had to be dealt with
> in the past when trying to model dynamic DDIs (vs, just taking one
> of the drugs as a covariate on the other’s parameters).
>
> One approach is to specify the compartments for each to be dosed
> into then have those feed the central, but I’m curious to see if
> there is something more subtle in the nonmem syntax. Is there
> something about EVID, that I don’t know that would help (beyond
> EVID=1 for dosing)
>
> What if you had two oral drugs? Would you treat the two dosing
> compartments as separate and possibly link them together at the
> parameter/covariance level?
>
> Thanks,
>
> Chris
>
> Chris Penland, PhD
>
> ECD / Quantitative Clinical Pharmacology
>
> Waltham, MA USA
>
> ------------------------------------------------------------------------
>
> *Confidentiality Notice: *This message is private and may contain
> confidential and proprietary information. If you have received
> this message in error, please notify us and remove it from your
> system and note that you must not copy, distribute or take any
> action in reliance on it. Any unauthorized use or disclosure of
> the contents of this message is not permitted and may be unlawful.
>
> Het Radboudumc staat geregistreerd bij de Kamer van Koophandel in het handelsregister onder nummer 41055629. The Radboud university medical center is listed in the Commercial Register of the Chamber of Commerce under file number 41055629.
Hi Chris,
I’ve done it, many years ago, for a drug-drug interaction to estimate an
inhibition constant for one drug on the clearance of the other. It was never
published, I was just playing around in my spare time to learn how to use
NONMEM. I’d developed a naïve pool model first in WinNonlin and SAAM II which
helped finding appropriate equations and with initial estimates.
As Nick suggested one can use ADVAN5 or 7 for linear systems (use matrix
calculations) which are faster than differentials (slower computers 16 years
ago). Use the first compartments for one drug, the subsequent for the other. If
Kij (see below) is not defined in the control file, it is set to a default of
zero.
All the best, Phil.
___________________________________________________________________
| |
| ADVAN5 ADVAN7 |
|_________________________________________________________________|
MEANING: Choice of Pharmacokinetic Model for PREDPP
CONTEXT: Option of NM-TRAN $SUBROUTINES record
USAGE:
$SUBROUTINES [ADVAN=]ADVAN5
SAMPLE:
$SUBROUTINE ADVAN5
DISCUSSION:
ADVAN5 and ADVAN7 are routines in PREDPP's library which implement the
general linear model. The general linear model is used for systems in
which a drug is distributed between compartments according to linear
processes. ADVAN7 may be used when the eigenvalues of the rate con-
stant matrix are known to be real (which is true for many pharmacok-
inetic systems such as mammillary models). It is generally faster
than ADVAN5.
A $MODEL record is required to describe the compartments and their
attributes. The $PK record (or, if a user-supplied PK routine is
used, the $MODEL record) describes how the compartments are linked.
TRANS routines that may be used: TRANS1
Suppose there are m compartments in the system, including the output
compartment.
Basic PK parameters with TRANS1:
Kij (rate constant from compartment i to compartment j)
Ki0 (alternate name for Kim)
The letter T may be used as a separator between the two compartment
numbers, e.g., KiTj. The letter T is optional when there is no
ambiguity, but required when there are two possible interpretations
of the numbers that follow K. E.g., with 12 compartments, K111 is
ambiguous. It should be coded K1T11 or K11T1, depending if it sym-
bolizes the rate constant from compartment 1 to compartment 11 or
from compartment 11 to compartment 1.
Additional PK parameters:
For each compartment n in the system (n=1, ..., m):
Sn - Scale for nth compartment
S0 - Alternate name for scale for output compartment
For each dosable compartment n in the system:
Fn - Bioavailability for nth compartment
Rn - Rate for nth compartment
Dn - Duration for nth compartment
ALAGn - Absorption lag for nth compartment
Other additional PK parameters:
F0 - Output fraction (also called Fm, FO)
XSCALE - X parameter
I second Leonid's approach, which is straightforward and scalable to more than
two drugs. Even when the two drugs don't interact at the PK level, this
approach could still be beneficial in quantifying the common physiological
processes that are perturbed by both drugs (if that's the case). I have an
example of estimating one set of system parameters based on the simultaneous
modeling of three different compounds from separate studies. The work is
currently under journal review and I'll be happy to share the code if
interested.
Thanks,
Cheng Chang, Ph.D.
Systems Modeling & Simulation
Department of Pharmacokinetics, Dynamics and Metabolism
Pfizer Inc.
Groton, CT
(860) 686-9240
Quoted reply history
-----Original Message-----
From: [email protected] [mailto:[email protected]] On
Behalf Of Leonid Gibiansky
Sent: Friday, September 2, 2016 4:01 PM
To: William Denney; Penland, Chris
Cc: [email protected]
Subject: Re: [NMusers] Simultaneous pk model of 2 drugs
I think there is no difference between simultaneous administration or not as
the dose is directed to the appropriate compartment using CMT variable. In any
case two dosing records (one for each drug) are needed, and the relative times
of these records are not important. So it is exactly like two models (one for
each drug) written in one control stream (with different compartments used for
each drug). CMT is used to direct the dose. DVID or CMT can be used to identify
observations for each drug. Interactions can be studied using correlations of
random effects, or using joint parameters, or directly specifying how
concentration of one drug influences the parameters of the other drug.
Regards,
Leonid
On 9/2/2016 3:01 PM, William Denney wrote:
> Hi Chris,
>
> I think that the most straight-forward way to handle this is to have
> two sets of compartments and write the $DES block manually (or writing
> the algebraic equations if it's a one- or two-compartment model).
>
> It wouldn't be straight-forward to model if the subjects receive the
> drugs at the same time. If the drugs are received at separate times
> (like different periods of a study or even different studies), then
> the DVID flag idea would work, too.
>
> There are only five EVID values as far as I know, and there's not a
> subtle way to use them for two doses, I don't think:
>
> • 0= observation
> • 1= dose
> • 2= other (I usually use it to reset the compartment) • 3= reset the
> subject • 4= reset and dose at the same time
>
> Thanks,
>
> Bill
>
> On Sep 2, 2016, at 1:22 PM, Penland, Chris
> <[email protected] <mailto:[email protected]>>
> wrote:
>
>> Greetings NMusers,
>>
>>
>>
>> Does nonmem have the capacity, unbeknownst to me, for modeling two
>> simultaneous drugs?
>>
>>
>>
>> I would like some suggestions about how to define the dataset and
>> model for a subcutaneous drug and oral drug being administered on
>> different schedules. I would use DVID = 1 and 2 for the two plasma pk
>> observations. I figure this soft of thing had to be dealt with in
>> the past when trying to model dynamic DDIs (vs, just taking one of
>> the drugs as a covariate on the other’s parameters).
>>
>>
>>
>> One approach is to specify the compartments for each to be dosed into
>> then have those feed the central, but I’m curious to see if there is
>> something more subtle in the nonmem syntax. Is there something about
>> EVID, that I don’t know that would help (beyond EVID=1 for dosing)
>>
>>
>>
>> What if you had two oral drugs? Would you treat the two dosing
>> compartments as separate and possibly link them together at the
>> parameter/covariance level?
>>
>>
>>
>> Thanks,
>>
>> Chris
>>
>>
>>
>>
>>
>> Chris Penland, PhD
>>
>> ECD / Quantitative Clinical Pharmacology
>>
>> Waltham, MA USA
>>
>>
>>
>> ---------------------------------------------------------------------
>> ---
>>
>> *Confidentiality Notice: *This message is private and may contain
>> confidential and proprietary information. If you have received this
>> message in error, please notify us and remove it from your system and
>> note that you must not copy, distribute or take any action in
>> reliance on it. Any unauthorized use or disclosure of the contents of
>> this message is not permitted and may be unlawful.
>>