Dear nmusers,
I'm working on the population PK of a therapeutic peptide candidate for
rheumatoid arthritis. Three dose levels of the peptide were administered as
a single subcutaneous injection.
We have some limitations, for instance, the dataset is very sparse and is
lacking in the information of the absorption phase. Some therapeutic
peptides have demonstrated flip-flop PK, specially those administered by
subcutaneous or intramuscular.
Is it possible to evaluate the flip-flop phenomenon without absorption
information?
I'll appreciate all your suggestions and advice.
Best,
Niurys
--
Niurys de Castro Suárez, PhD
Assistant Professor of Pharmacometrics
Associate Research
Pharmacy Department
Institute of Pharmacy and Food,
University of Havana
Cuba
"Una estrella brilla en la hora de nuestro encuentro"
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
Quoted reply history
> On 13 Sep 2022, at 05:05, Niurys.CS <[email protected]> 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 https://pharmetheus.com/privacy-policy/.**
*
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
Quoted reply history
On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing <[email protected]>
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 <[email protected]> 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 https://pharmetheus.com/privacy-policy/.*
>
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 <[email protected]>:
> 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
>
Quoted reply history
> On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing <
> [email protected]> 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 <[email protected]> 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 https://pharmetheus.com/privacy-policy/.*
>>
>
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
Quoted reply history
Van: [email protected] <[email protected]> Namens Jakob
Ribbing
Verzonden: dinsdag 13 september 2022 06:23
Aan: Niurys.CS <[email protected]>; nmusers <[email protected]>
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
<[email protected]<mailto:[email protected]>> 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
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fpharmetheus.com%2Fprivacy-policy%2F&data=05%7C01%7Cd.j.eleveld%40umcg.nl%7Cd9d9d66771e044080b8908da9540f3ac%7C335122f9d4f44d67a2fccd6dc20dde70%7C0%7C0%7C637986403439146794%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Va6LIYK0s9Pkvv4AL9e%2FQ0dxdVwOgUBaSFhsU81dTAY%3D&reserved=0.
________________________________
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
[email protected]<mailto:[email protected]>
(224) 619-4901
Quote of the week –
“Dancing with the Stars” is not owned by Astellas.
Quoted reply history
From: [email protected] <[email protected]> On Behalf Of
Shan Pan
Sent: Tuesday, September 13, 2022 3:42 AM
To: Jakob Ribbing <[email protected]>; Niurys.CS
<[email protected]>
Cc: nmusers <[email protected]>
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
<[email protected]<mailto:[email protected]>> 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
<[email protected]<mailto:[email protected]>> 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 https://pharmetheus.com/privacy-policy/.
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
Quoted reply history
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
>
> [email protected] <mailto:[email protected]>
>
> (224) 619-4901
>
> Quote of the week –
>
> /“Dancing with the Stars” is not owned by Astellas.**/
>
> *From:* [email protected] < [email protected] > *On Behalf Of *Shan Pan
>
> *Sent:* Tuesday, September 13, 2022 3:42 AM
>
> *To:* Jakob Ribbing < [email protected] >; Niurys.CS < [email protected] >
>
> *Cc:* nmusers <[email protected]>
> *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 < [email protected] < mailto: [email protected] >> 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 <[email protected]
> <mailto:[email protected]>> 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/
> https://pharmetheus.com/privacy-policy//./
Dear all,
thank you so. I think it is necessary to take into account all these
explanations and suggestions as well before building the Pop PK model for
this peptide.
I don't have any dataset from previous IV administration, and, as I
mentioned in my email, the current dataset is lacking in information of
absorption phase.
Best,
Niurys
Quoted reply history
El mar, 13 sept 2022 a las 17:46, Leonid Gibiansky (<
[email protected]>) escribió:
> 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
> >
> > [email protected] <mailto:[email protected]>
> >
> > (224) 619-4901
> >
> > Quote of the week –
> >
> > /“Dancing with the Stars” is not owned by Astellas.**/
> >
> > *From:* [email protected] <[email protected]> *On
> > Behalf Of *Shan Pan
> > *Sent:* Tuesday, September 13, 2022 3:42 AM
> > *To:* Jakob Ribbing <[email protected]>; Niurys.CS
> > <[email protected]>
> > *Cc:* nmusers <[email protected]>
> > *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
> > <[email protected] <mailto:[email protected]>>
> > 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 <[email protected]
> > <mailto:[email protected]>> 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/
> > https://pharmetheus.com/privacy-policy//./
> >
>
>
--
Niurys de Castro Suárez, PhD
Assistant Professor of Pharmacometrics
Associate Research
Pharmacy Department
Institute of Pharmacy and Food,
University of Havana
Cuba
"Una estrella brilla en la hora de nuestro encuentro"