Re: [NMusers] data

[Philip Harder Delff]

Hi Andre,

It seems like you got the help you needed. I just want to bring to your 
attention that the R package NMdata provides a function called 
NMcheckData that can scan a data set for compatibility with Nonmem and 
additional pitfalls for PK or PK/PD data sets. Admittedly, it would 
report a finding if MDV=1 and DV<0.


Sometimes the problems occur because the the $INPUT section in the 
control stream has a different order of columns than the data set. If 
you pass a control stream as

NMcheckData(file=)
it will read the data as defined in the control stream, compare to 
column names (if found) in the input data file, and then turn to 
checking the data set for nonmem compatibility. So if something weird is 
going on, that can very often point you to where and why.


Best,
Philip

On 9/5/22 10:41, jacksonan1...@gmail.com wrote:

All:

I have data which looks like this with the line number inserted in ( ).

WSUBJ  TIME CP  MDV CTIME   DAY   AMT  EVID  DV

(1)1   0    0    0    0
1    0.001    1    0.153846


(12)2 0    0    0    0
1    0.001    1    -0.30769


(21)3 0    0    0    0
1    0.001    1    1.076923


I get the following warning with each run.

(DATA WARNING 5) RECORD  1, DATA ITEM 9, CONTENTS 0.1538

THE DV DATA ITEM IS POSITIVE, BUT THE MDV ITEM IS 1

(DATA WARNING 5) RECORD  21, DATA ITEM 9, CONTENTS 1.0769

THE DV DATA ITEM IS POSITIVE, BUT THE MDV ITEM IS 1

Each is a dosing for PD; however, it does not happen for record 12, also 
a dosing record.  Can someone tell me why,  and how to address this issue?

Re: [NMusers] flip-flop without absorption information?

[Leonid Gibiansky]

With flip-flop, we always can get 2 solutions (assuming 1-cmpt model 
with absorption; 2-cpt case is similar but expressions may differ):


ka1-CL-V1 and ka2-CL-V2 such that

ka1=CL/V2 and ka2=CL/V1

Note that CL is the same, so info on CL will not help to distinguish 
these cases.


One cannot just fix the volume, as it should have one of the values V1 
or V2, but one can select the "more mechanistic" value if other 
information (e.g., about similar compounds) is available, and push the 
solution to the right place by providing the bounds on the range of 
possible parameter estimates.


Note that with SC dose, we cannot estimate CL and V, we have apparent CL 
and apparent V (related to the underlying CLtrue and Vtrue as 
CL=CLtrue/F and V= Vtrue/F, where F is the absolute bioavailability of 
SC administration). When apparent CL and apparent V are compared with 
parameters for other compounds, F should be taken into account.


Thank you
Leonid




On 9/13/2022 10:54 AM, Bonate, Peter wrote:

In comment to Shan’s statement:

It's my understanding that this flip-flop phenomenon is fundamentally a 
mathematical problem -- that is, if we write down a PK model in its 
analytical form, it becomes rather easy to understand that swapping the 
values between ka and ke (CL/V) would lead to the same output.


This is not true.  The values do not swap out.  V will be different.

Consider a 1-compartment model with KA=0.1 per h, KEL=0.7 per h, and 
V1=125L.  Suppose a 250 mg dose is given.  This model has flip-flop 
kinetics.


Now assume we build a model with KA=0.7 per h, KEL=0.1 per h, and V2 is 
unknown, same dose. This model does not have flip-flop. Using the 
simulated data from model 1 as the observed data for model 2, we can fit 
model 2 and find the optimum value of V2.  In this case it is 875L.  If 
you look at the profiles you will see that they are /exactly/ the same.


So it’s not a matter of just changing the order of the exponents.

If you want to estimate the parameters of a flip-flop model you need a 
data without absorption – IV.  Or some other independent assessment of 
CL that does not depend on absorption.


*Peter Bonate, PhD*

Executive Director

Pharmacokinetics, Modeling, and Simulation (PKMS)

Clinical Pharmacology and Exploratory Development (CPED)

Astellas

1 Astellas Way

Northbrook, IL  60062

peter.bon...@astellas.com 

(224) 619-4901

Quote of the week –

/“Dancing with the Stars” is not owned by Astellas.**/

*From:* owner-nmus...@globomaxnm.com  *On 
Behalf Of *Shan Pan

*Sent:* Tuesday, September 13, 2022 3:42 AM
*To:* Jakob Ribbing ; Niurys.CS 


*Cc:* nmusers 
*Subject:* Re: [NMusers] flip-flop without absorption information?

This is an interesting discussion. At the same time I can't get my head 
around the assumption of any covariate on a flip-flop phenomenon. In 
other words, even if there is no information on covariates 
this phenomenon could still exist.


It's my understanding that this flip-flop phenomenon is fundamentally a 
mathematical problem -- that is, if we write down a PK model in its 
analytical form, it becomes rather easy to understand that swapping the 
values between ka and ke (CL/V) would lead to the same output.


In the absence of data on drug absorption as in your case, I think the 
solution could lie in fixing volume of distribution based on any prior 
information, e.g. a reported value in the literature. Otherwise, try to 
fix it to a reasonable estimate and see what happens.


Hope it helps.

Kind regards,

Shan

On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing 
mailto:jakob.ribb...@pharmetheus.com>> 
wrote:


Dear Niurys,

It would be down to distributional assumptions in that case.

For example if you have a very strong predictor (covariate) of
either elimination or absorption rate (but not both) - data could be
informative to discriminate between flip-flop or not.

Had your therapeutic been IgG monoclonal antibody, albumin wold have
been a predictor of the absolute CL that with a larger number of
subjects may allow to discriminate (especially if a mix of both
healthy, and patients with higher inflammation level and thereby
lower albumin -> higher CL).

On the other hand, for example body weight would not be helpful in
this regard.

Even if body weight would have an effect on CL and V, it would not
have a major impact on terminal elimination (and in addition one
could have a concern on body weight also affecting the absorption rate).

So you would need both the mechanistic knowledge on the covariate,
for your therapeutic peptide in the RA population, and it would need
to be a strong effect in sufficient number of subjects.

On such obvious covariate would be different routes of
administration, where nobody would question the mechanistic
knowledge on that SC has a slower absorption that IV :>)

In liu of IV dosing this becomes a more 

Re: [NMusers] flip-flop without absorption information?

[Shan Pan]

Correct -- I totally agree with what you said about the change of the value
of volume of distribution once ka and ke values are exchanged in order to
obtain identical time-conc profiles.

At the same time, it also points to the solution in particular* in the
absence of any IV data* -- fixing the value of volume of distribution.
Correct me if I am wrong.


On Tue, Sep 13, 2022 at 4:07 PM Bonate, Peter 
wrote:

> In comment to Shan’s statement:
>
>
>
> It's my understanding that this flip-flop phenomenon is fundamentally a
> mathematical problem -- that is, if we write down a PK model in its
> analytical form, it becomes rather easy to understand that swapping the
> values between ka and ke (CL/V) would lead to the same output.
>
>
>
> This is not true.  The values do not swap out.  V will be different.
>
>
>
> Consider a 1-compartment model with KA=0.1 per h, KEL=0.7 per h, and
> V1=125L.  Suppose a 250 mg dose is given.  This model has flip-flop
> kinetics.
>
>
>
> Now assume we build a model with KA=0.7 per h, KEL=0.1 per h, and V2 is
> unknown, same dose. This model does not have flip-flop. Using the simulated
> data from model 1 as the observed data for model 2, we can fit model 2 and
> find the optimum value of V2.  In this case it is 875L.  If you look at the
> profiles you will see that they are *exactly* the same.
>
>
>
> So it’s not a matter of just changing the order of the exponents.
>
>
>
> If you want to estimate the parameters of a flip-flop model you need a
> data without absorption – IV.  Or some other independent assessment of CL
> that does not depend on absorption.
>
>
>
>
>
>
>
> *Peter Bonate, PhD*
>
> Executive Director
>
> Pharmacokinetics, Modeling, and Simulation (PKMS)
>
> Clinical Pharmacology and Exploratory Development (CPED)
>
> Astellas
>
> 1 Astellas Way
>
> Northbrook, IL  60062
>
> peter.bon...@astellas.com
>
> (224) 619-4901
>
>
>
>
>
> Quote of the week –
>
> *“Dancing with the Stars” is not owned by Astellas.*
>
>
>
> *From:* owner-nmus...@globomaxnm.com  *On
> Behalf Of *Shan Pan
> *Sent:* Tuesday, September 13, 2022 3:42 AM
> *To:* Jakob Ribbing ; Niurys.CS <
> amaranth...@gmail.com>
> *Cc:* nmusers 
> *Subject:* Re: [NMusers] flip-flop without absorption information?
>
>
>
> This is an interesting discussion. At the same time I can't get my head
> around the assumption of any covariate on a flip-flop phenomenon. In other
> words, even if there is no information on covariates this phenomenon could
> still exist.
>
>
>
> It's my understanding that this flip-flop phenomenon is fundamentally a
> mathematical problem -- that is, if we write down a PK model in its
> analytical form, it becomes rather easy to understand that swapping the
> values between ka and ke (CL/V) would lead to the same output.
>
>
>
> In the absence of data on drug absorption as in your case, I think the
> solution could lie in fixing volume of distribution based on any prior
> information, e.g. a reported value in the literature. Otherwise, try to fix
> it to a reasonable estimate and see what happens.
>
>
>
> Hope it helps.
>
>
>
> Kind regards,
>
> Shan
>
>
>
> On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing <
> jakob.ribb...@pharmetheus.com> wrote:
>
> Dear Niurys,
>
>
>
> It would be down to distributional assumptions in that case.
>
> For example if you have a very strong predictor (covariate) of either
> elimination or absorption rate (but not both) - data could be informative
> to discriminate between flip-flop or not.
>
>
>
> Had your therapeutic been IgG monoclonal antibody, albumin wold have been
> a predictor of the absolute CL that with a larger number of subjects may
> allow to discriminate (especially if a mix of both healthy, and patients
> with higher inflammation level and thereby lower albumin -> higher CL).
>
> On the other hand, for example body weight would not be helpful in this
> regard.
>
> Even if body weight would have an effect on CL and V, it would not have a
> major impact on terminal elimination (and in addition one could have a
> concern on body weight also affecting the absorption rate).
>
>
>
> So you would need both the mechanistic knowledge on the covariate, for
> your therapeutic peptide in the RA population, and it would need to be a
> strong effect in sufficient number of subjects.
>
> On such obvious covariate would be different routes of administration,
> where nobody would question the mechanistic knowledge on that SC has a
> slower absorption that IV :>)
>
> In liu of IV dosing this becomes a more challenging task, however.
>
>
>
> Best wishes
>
>
>
> Jakob
>
>
>
>
>
>
>
> On 13 Sep 2022, at 05:05, Niurys.CS  wrote:
>
>
>
> Niurys
>
>
>
>
>
> *This communication is confidential and is only intended for the use of
> the individual or entity to which it is directed. It may contain
> information that is privileged and exempt from disclosure under applicable
> law. If you are not the intended recipient please notify us immediately.
> Please do not copy it or 

RE: [NMusers] flip-flop without absorption information?

[Bonate, Peter]

In comment to Shan’s statement:

It's my understanding that this flip-flop phenomenon is fundamentally a 
mathematical problem -- that is, if we write down a PK model in its analytical 
form, it becomes rather easy to understand that swapping the values between ka 
and ke (CL/V) would lead to the same output.

This is not true.  The values do not swap out.  V will be different.

Consider a 1-compartment model with KA=0.1 per h, KEL=0.7 per h, and V1=125L.  
Suppose a 250 mg dose is given.  This model has flip-flop kinetics.

Now assume we build a model with KA=0.7 per h, KEL=0.1 per h, and V2 is 
unknown, same dose. This model does not have flip-flop. Using the simulated 
data from model 1 as the observed data for model 2, we can fit model 2 and find 
the optimum value of V2.  In this case it is 875L.  If you look at the profiles 
you will see that they are exactly the same.

So it’s not a matter of just changing the order of the exponents.

If you want to estimate the parameters of a flip-flop model you need a data 
without absorption – IV.  Or some other independent assessment of CL that does 
not depend on absorption.



Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS)
Clinical Pharmacology and Exploratory Development (CPED)
Astellas
1 Astellas Way
Northbrook, IL  60062
peter.bon...@astellas.com
(224) 619-4901


Quote of the week –
“Dancing with the Stars” is not owned by Astellas.

From: owner-nmus...@globomaxnm.com  On Behalf Of 
Shan Pan
Sent: Tuesday, September 13, 2022 3:42 AM
To: Jakob Ribbing ; Niurys.CS 

Cc: nmusers 
Subject: Re: [NMusers] flip-flop without absorption information?

This is an interesting discussion. At the same time I can't get my head around 
the assumption of any covariate on a flip-flop phenomenon. In other words, even 
if there is no information on covariates this phenomenon could still exist.

It's my understanding that this flip-flop phenomenon is fundamentally a 
mathematical problem -- that is, if we write down a PK model in its analytical 
form, it becomes rather easy to understand that swapping the values between ka 
and ke (CL/V) would lead to the same output.

In the absence of data on drug absorption as in your case, I think the solution 
could lie in fixing volume of distribution based on any prior information, e.g. 
a reported value in the literature. Otherwise, try to fix it to a reasonable 
estimate and see what happens.

Hope it helps.

Kind regards,
Shan

On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing 
mailto:jakob.ribb...@pharmetheus.com>> wrote:
Dear Niurys,

It would be down to distributional assumptions in that case.
For example if you have a very strong predictor (covariate) of either 
elimination or absorption rate (but not both) - data could be informative to 
discriminate between flip-flop or not.

Had your therapeutic been IgG monoclonal antibody, albumin wold have been a 
predictor of the absolute CL that with a larger number of subjects may allow to 
discriminate (especially if a mix of both healthy, and patients with higher 
inflammation level and thereby lower albumin -> higher CL).
On the other hand, for example body weight would not be helpful in this regard.
Even if body weight would have an effect on CL and V, it would not have a major 
impact on terminal elimination (and in addition one could have a concern on 
body weight also affecting the absorption rate).

So you would need both the mechanistic knowledge on the covariate, for your 
therapeutic peptide in the RA population, and it would need to be a strong 
effect in sufficient number of subjects.
On such obvious covariate would be different routes of administration, where 
nobody would question the mechanistic knowledge on that SC has a slower 
absorption that IV :>)
In liu of IV dosing this becomes a more challenging task, however.

Best wishes

Jakob




On 13 Sep 2022, at 05:05, Niurys.CS 
mailto:amaranth...@gmail.com>> wrote:

Niurys


This communication is confidential and is only intended for the use of the 
individual or entity to which it is directed. It may contain information that 
is privileged and exempt from disclosure under applicable law. If you are not 
the intended recipient please notify us immediately. Please do not copy it or 
disclose its contents to any other person.
Any personal data will be processed in accordance with Pharmetheus' privacy 
notice, available here.

RE: [NMusers] flip-flop without absorption information?

[Eleveld, DJ]

Hi Jakob and Everyone,

In the no-covariate case flip and flop  represent equal likelihoods i.e. two 
local minimums of equal depth.
I agree that distributional assumptions would likely be useful to discriminate 
between two different parameters values that have equal likelihoods.
Depending on how much information is contained in the covariate then minimum 
might “shift” so that one becomes the global minimum and the other a local 
minimum.
But one should be aware that local minimums could be present and influence 
NONMEM estimation.

Warm regards,

Douglas


Van: owner-nmus...@globomaxnm.com  Namens Jakob 
Ribbing
Verzonden: dinsdag 13 september 2022 06:23
Aan: Niurys.CS ; nmusers 
Onderwerp: Re: [NMusers] flip-flop without absorption information?

Dear Niurys,

It would be down to distributional assumptions in that case.
For example if you have a very strong predictor (covariate) of either 
elimination or absorption rate (but not both) - data could be informative to 
discriminate between flip-flop or not.

Had your therapeutic been IgG monoclonal antibody, albumin wold have been a 
predictor of the absolute CL that with a larger number of subjects may allow to 
discriminate (especially if a mix of both healthy, and patients with higher 
inflammation level and thereby lower albumin -> higher CL).
On the other hand, for example body weight would not be helpful in this regard.
Even if body weight would have an effect on CL and V, it would not have a major 
impact on terminal elimination (and in addition one could have a concern on 
body weight also affecting the absorption rate).

So you would need both the mechanistic knowledge on the covariate, for your 
therapeutic peptide in the RA population, and it would need to be a strong 
effect in sufficient number of subjects.
On such obvious covariate would be different routes of administration, where 
nobody would question the mechanistic knowledge on that SC has a slower 
absorption that IV :>)
In liu of IV dosing this becomes a more challenging task, however.

Best wishes

Jakob




On 13 Sep 2022, at 05:05, Niurys.CS 
mailto:amaranth...@gmail.com>> wrote:

Niurys


This communication is confidential and is only intended for the use of the 
individual or entity to which it is directed. It may contain information that 
is privileged and exempt from disclosure under applicable law. If you are not 
the intended recipient please notify us immediately. Please do not copy it or 
disclose its contents to any other person.
Any personal data will be processed in accordance with Pharmetheus' privacy 
notice, available 
here.

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Re: [NMusers] flip-flop without absorption information?

[Wilbert de Witte]

Hi Niurys,

Depending on the size of your peptide and the timing of the first
observations, it might also be likely that the rate limiting step for the
terminal elimination phase is the (re)distribution from the peripheral to
the central compartment, rather than the absorption.
This is nicely demonstrated for small proteins in figure 3 of this paper by
Li and Shah, where you see the impact of size mainly on the initial phase
of the PK curves, rather than the elimination phase, and this is nicely
captured by the PBPK model.
https://pubmed.ncbi.nlm.nih.gov/31028591/
Coming back to your question if this can be evaluated without data in the
first phase, you would need other information on the clearance. This could
be derived from covariate relationships as Jakob suggested, or from prior
knowledge on the expected Clearance. You could use, for example, the
assumption that the clearance is equal to the GFR and see how that relates
to your data, possibly extended with absorption/distribution parameters
based on the two-pore model (and the molecular weight).
Best,

Wilbert de Witte


Op di 13 sep. 2022 om 10:53 schreef Shan Pan :

> This is an interesting discussion. At the same time I can't get my head
> around the assumption of any covariate on a flip-flop phenomenon. In other
> words, even if there is no information on covariates this phenomenon could
> still exist.
>
> It's my understanding that this flip-flop phenomenon is fundamentally a
> mathematical problem -- that is, if we write down a PK model in its
> analytical form, it becomes rather easy to understand that swapping the
> values between ka and ke (CL/V) would lead to the same output.
>
> In the absence of data on drug absorption as in your case, I think the
> solution could lie in fixing volume of distribution based on any prior
> information, e.g. a reported value in the literature. Otherwise, try to fix
> it to a reasonable estimate and see what happens.
>
> Hope it helps.
>
> Kind regards,
> Shan
>
> On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing <
> jakob.ribb...@pharmetheus.com> wrote:
>
>> Dear Niurys,
>>
>> It would be down to distributional assumptions in that case.
>> For example if you have a very strong predictor (covariate) of either
>> elimination or absorption rate (but not both) - data could be informative
>> to discriminate between flip-flop or not.
>>
>> Had your therapeutic been IgG monoclonal antibody, albumin wold have been
>> a predictor of the absolute CL that with a larger number of subjects may
>> allow to discriminate (especially if a mix of both healthy, and patients
>> with higher inflammation level and thereby lower albumin -> higher CL).
>> On the other hand, for example body weight would not be helpful in this
>> regard.
>> Even if body weight would have an effect on CL and V, it would not have a
>> major impact on terminal elimination (and in addition one could have a
>> concern on body weight also affecting the absorption rate).
>>
>> So you would need both the mechanistic knowledge on the covariate, for
>> your therapeutic peptide in the RA population, and it would need to be a
>> strong effect in sufficient number of subjects.
>> On such obvious covariate would be different routes of administration,
>> where nobody would question the mechanistic knowledge on that SC has a
>> slower absorption that IV :>)
>> In liu of IV dosing this becomes a more challenging task, however.
>>
>> Best wishes
>>
>> Jakob
>>
>>
>>
>>
>>
>> On 13 Sep 2022, at 05:05, Niurys.CS  wrote:
>>
>> Niurys
>>
>>
>>
>> *This communication is confidential and is only intended for the use of
>> the individual or entity to which it is directed. It may contain
>> information that is privileged and exempt from disclosure under applicable
>> law. If you are not the intended recipient please notify us immediately.
>> Please do not copy it or disclose its contents to any other person.*
>> *Any personal data will be processed in accordance with Pharmetheus'
>> privacy notice, available here .*
>>
>

Re: [NMusers] flip-flop without absorption information?

[Shan Pan]

This is an interesting discussion. At the same time I can't get my head
around the assumption of any covariate on a flip-flop phenomenon. In other
words, even if there is no information on covariates this phenomenon could
still exist.

It's my understanding that this flip-flop phenomenon is fundamentally a
mathematical problem -- that is, if we write down a PK model in its
analytical form, it becomes rather easy to understand that swapping the
values between ka and ke (CL/V) would lead to the same output.

In the absence of data on drug absorption as in your case, I think the
solution could lie in fixing volume of distribution based on any prior
information, e.g. a reported value in the literature. Otherwise, try to fix
it to a reasonable estimate and see what happens.

Hope it helps.

Kind regards,
Shan

On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing 
wrote:

> Dear Niurys,
>
> It would be down to distributional assumptions in that case.
> For example if you have a very strong predictor (covariate) of either
> elimination or absorption rate (but not both) - data could be informative
> to discriminate between flip-flop or not.
>
> Had your therapeutic been IgG monoclonal antibody, albumin wold have been
> a predictor of the absolute CL that with a larger number of subjects may
> allow to discriminate (especially if a mix of both healthy, and patients
> with higher inflammation level and thereby lower albumin -> higher CL).
> On the other hand, for example body weight would not be helpful in this
> regard.
> Even if body weight would have an effect on CL and V, it would not have a
> major impact on terminal elimination (and in addition one could have a
> concern on body weight also affecting the absorption rate).
>
> So you would need both the mechanistic knowledge on the covariate, for
> your therapeutic peptide in the RA population, and it would need to be a
> strong effect in sufficient number of subjects.
> On such obvious covariate would be different routes of administration,
> where nobody would question the mechanistic knowledge on that SC has a
> slower absorption that IV :>)
> In liu of IV dosing this becomes a more challenging task, however.
>
> Best wishes
>
> Jakob
>
>
>
>
>
> On 13 Sep 2022, at 05:05, Niurys.CS  wrote:
>
> Niurys
>
>
>
> *This communication is confidential and is only intended for the use of
> the individual or entity to which it is directed. It may contain
> information that is privileged and exempt from disclosure under applicable
> law. If you are not the intended recipient please notify us immediately.
> Please do not copy it or disclose its contents to any other person.*
> *Any personal data will be processed in accordance with Pharmetheus'
> privacy notice, available here .*
>