Dear all
I need some help to assess the elimination half life of a monoclonal
antibody.
The model that describes the data is a QSS aproximation of TMDD with Rmax
constant. The model includes two binding process of mAb to its target: in
central and peripheral compartments.
Is there any specific equation to calcule lambda z and the elimination half
life for each of the TMDD aproximations?
Thanks
Niurys
Assessment of elimination half life of mAb
There is no such thing as half-life of elimination for the nonlinear drug. But one can compute something like half-life:
1. Half-life of the linear part (defined by CL, V1, V2, Q): this defines the half-life at high doses/high concentrations when nonlinear elimination is saturated.
2. Washout time: for the linear drug, 5 half-lives can be used to define washout time. During this time, concentrations drop approximately 2^5=32 times. So one can simulate the desired dosing (single dose or steady state), find the time from Cmax to Cmax/32 and call it washout time (or time to Cmax/64 to be conservative)
Thanks
Leonid
Quoted reply history
On 4/28/2021 5:17 PM, Niurys.CS wrote:
> Dear all
>
> I need some help to assess the elimination half life of a monoclonal antibody. The model that describes the data is a QSS aproximation of TMDD with Rmax constant. The model includes two binding process of mAb to its target: in central and peripheral compartments. Is there any specific equation to calcule lambda z and the elimination half life for each of the TMDD aproximations?
>
> Thanks
> Niurys
Dear Leonid,
Many thanks for clearing up my doubt. Can you suggest me any paper to go
into this topic in any depth.
Best,
Niurys
Quoted reply history
El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]>
escribió:
> There is no such thing as half-life of elimination for the nonlinear drug.
> But one can compute something like half-life:
>
> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this defines
> the half-life at high doses/high concentrations when nonlinear elimination
> is saturated.
>
> 2. Washout time: for the linear drug, 5 half-lives can be used to define
> washout time. During this time, concentrations drop approximately 2^5=32
> times. So one can simulate the desired dosing (single dose or steady
> state), find the time from Cmax to Cmax/32 and call it washout time (or
> time to Cmax/64 to be conservative)
>
> Thanks
> Leonid
>
>
> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>
>> Dear all
>> I need some help to assess the elimination half life of a monoclonal
>> antibody.
>> The model that describes the data is a QSS aproximation of TMDD with Rmax
>> constant. The model includes two binding process of mAb to its target: in
>> central and peripheral compartments.
>> Is there any specific equation to calcule lambda z and the elimination
>> half life for each of the TMDD aproximations?
>> Thanks
>> Niurys
>>
>>
I am not aware of any papers specifically addressing the half-live issue, but there are tons of original papers and tutorials on TMDD, just search the web
Thanks
Leonid
Quoted reply history
On 4/29/2021 9:48 AM, Niurys.CS wrote:
> Dear Leonid,
>
> Many thanks for clearing up my doubt. Can you suggest me any paper to go into this topic in any depth.
>
> Best,
> Niurys
>
> El 28/04/2021 19:34, "Leonid Gibiansky" < [email protected] < mailto: [email protected] >> escribió:
>
> There is no such thing as half-life of elimination for the nonlinear
> drug. But one can compute something like half-life:
>
> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
> defines the half-life at high doses/high concentrations when
> nonlinear elimination is saturated.
>
> 2. Washout time: for the linear drug, 5 half-lives can be used to
> define washout time. During this time, concentrations drop
> approximately 2^5=32 times. So one can simulate the desired dosing
> (single dose or steady state), find the time from Cmax to Cmax/32
> and call it washout time (or time to Cmax/64 to be conservative)
>
> Thanks
> Leonid
>
> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>
> Dear all
> I need some help to assess the elimination half life of a
> monoclonal antibody.
> The model that describes the data is a QSS aproximation of TMDD
> with Rmax constant. The model includes two binding process of
> mAb to its target: in central and peripheral compartments.
> Is there any specific equation to calcule lambda z and the
> elimination half life for each of the TMDD aproximations?
> Thanks
> Niurys
I've never really been happy with this. It's an unsatisfactory solution. You
have a nonlinear drug. Let's assume you have an approved drug. It's given at
some fixed dose. The clinician wants to know what is the drug's half-life so
they can washout their patient and start them on some other therapy. We go
back to them and say, we can't give you a half-life because it's a nonlinear
drug, but once the kinetics become linear the half-life is X hours. That is a
terrible answer. Maybe we need to come up with a new term, call it C90, the
time it takes for Cmax to decline by 90%. That we can do. We don't even need
an analytical solution, we can eyeball it. We could even get fancy and do it
in a population model. C90 - the time it takes for Cmax to decline 90% in 90%
of patients. Of course, for nonlinear drugs, C90 only holds for that dose.
Change in dose results in a new C90. Just a thought.
pete
Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS)
Clinical Pharmacology and Exploratory Development (CPED)
Astellas
1 Astellas Way, N3.158
Northbrook, IL 60062
[email protected]
(224) 619-4901
It’s been a while since I’ve had something here, but here is a Dad joke.
Question: Do you know why the math book was sad?
Answer: Because it had so many problems
Quoted reply history
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Leonid Gibiansky
Sent: Thursday, April 29, 2021 9:54 AM
To: Niurys.CS <[email protected]>
Cc: [email protected]
Subject: Re: [NMusers] Assessment of elimination half life of mAb
I am not aware of any papers specifically addressing the half-live issue, but
there are tons of original papers and tutorials on TMDD, just search the web
Thanks Leonid
On 4/29/2021 9:48 AM, Niurys.CS wrote:
> Dear Leonid,
>
> Many thanks for clearing up my doubt. Can you suggest me any paper to
> go into this topic in any depth.
> Best,
> Niurys
>
> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
> <mailto:[email protected]>> escribió:
>
> There is no such thing as half-life of elimination for the nonlinear
> drug. But one can compute something like half-life:
>
> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
> defines the half-life at high doses/high concentrations when
> nonlinear elimination is saturated.
>
> 2. Washout time: for the linear drug, 5 half-lives can be used to
> define washout time. During this time, concentrations drop
> approximately 2^5=32 times. So one can simulate the desired dosing
> (single dose or steady state), find the time from Cmax to Cmax/32
> and call it washout time (or time to Cmax/64 to be conservative)
>
> Thanks
> Leonid
>
>
> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>
> Dear all
> I need some help to assess the elimination half life of a
> monoclonal antibody.
> The model that describes the data is a QSS aproximation of TMDD
> with Rmax constant. The model includes two binding process of
> mAb to its target: in central and peripheral compartments.
> Is there any specific equation to calcule lambda z and the
> elimination half life for each of the TMDD aproximations?
> Thanks
> Niurys
>
Hi Pete,
I agree that it is hard to communicate. I like the general idea of C90 you
propose. I tend to choose something in between your and Leonid's answer,
when possible. I target an answer of "when is the pharmacodynamic effect
<5% of the maximum or therapeutic effect". It does require more than just
the PK, though. And for the just PK answer, I agree with Leonid and you,
targeting some smallish fraction of Cmax is often reasonable for similar
communication.
What I find clinicians typically try to understand when the drug has washed
out. The answer that many have reasonably latched onto is when 5 half-lives
have passed, the drug is washed out. That suggests that about 3% (2^-5)
effect is generally agreed as being washed out.
To Niurys's question about a citation for this, I don't have one either.
It's just a rule-of-thumb that I have tended to use.
Thanks,
Bill
Quoted reply history
-----Original Message-----
From: [email protected] <[email protected]> On Behalf
Of Bonate, Peter
Sent: Thursday, April 29, 2021 12:01 PM
To: Leonid Gibiansky <[email protected]>; Niurys.CS
<[email protected]>
Cc: [email protected]
Subject: RE: [NMusers] Assessment of elimination half life of mAb
I've never really been happy with this. It's an unsatisfactory solution.
You have a nonlinear drug. Let's assume you have an approved drug. It's
given at some fixed dose. The clinician wants to know what is the drug's
half-life so they can washout their patient and start them on some other
therapy. We go back to them and say, we can't give you a half-life because
it's a nonlinear drug, but once the kinetics become linear the half-life is
X hours. That is a terrible answer. Maybe we need to come up with a new
term, call it C90, the time it takes for Cmax to decline by 90%. That we
can do. We don't even need an analytical solution, we can eyeball it. We
could even get fancy and do it in a population model. C90 - the time it
takes for Cmax to decline 90% in 90% of patients. Of course, for nonlinear
drugs, C90 only holds for that dose. Change in dose results in a new C90.
Just a thought.
pete
Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical Pharmacology and
Exploratory Development (CPED) Astellas
1 Astellas Way, N3.158
Northbrook, IL 60062
[email protected]
(224) 619-4901
It’s been a while since I’ve had something here, but here is a Dad joke.
Question: Do you know why the math book was sad?
Answer: Because it had so many problems
-----Original Message-----
From: [email protected] <[email protected]> On Behalf
Of Leonid Gibiansky
Sent: Thursday, April 29, 2021 9:54 AM
To: Niurys.CS <[email protected]>
Cc: [email protected]
Subject: Re: [NMusers] Assessment of elimination half life of mAb
I am not aware of any papers specifically addressing the half-live issue,
but there are tons of original papers and tutorials on TMDD, just search the
web Thanks Leonid
On 4/29/2021 9:48 AM, Niurys.CS wrote:
> Dear Leonid,
>
> Many thanks for clearing up my doubt. Can you suggest me any paper to
> go into this topic in any depth.
> Best,
> Niurys
>
> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
> <mailto:[email protected]>> escribió:
>
> There is no such thing as half-life of elimination for the nonlinear
> drug. But one can compute something like half-life:
>
> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
> defines the half-life at high doses/high concentrations when
> nonlinear elimination is saturated.
>
> 2. Washout time: for the linear drug, 5 half-lives can be used to
> define washout time. During this time, concentrations drop
> approximately 2^5=32 times. So one can simulate the desired dosing
> (single dose or steady state), find the time from Cmax to Cmax/32
> and call it washout time (or time to Cmax/64 to be conservative)
>
> Thanks
> Leonid
>
>
> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>
> Dear all
> I need some help to assess the elimination half life of a
> monoclonal antibody.
> The model that describes the data is a QSS aproximation of TMDD
> with Rmax constant. The model includes two binding process of
> mAb to its target: in central and peripheral compartments.
> Is there any specific equation to calcule lambda z and the
> elimination half life for each of the TMDD aproximations?
> Thanks
> Niurys
>
To Bill and Pete and all -
Just adding my experience
I agree that a simulation based "time - to - x%" endpoint are very useful. -
half life means very little or is distracting.
Myself, I have used such simulations to establish label language for
prescribers for an injectable product with release-limited kinetics -
We used time to reach 10% of steady state concentration, this was also near BLQ.
It also plays a role in safety monitoring of overdose cases - how long do you
need to watch someone for.
Best regards,
Chris
Quoted reply history
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Bill Denney
Sent: Thursday, April 29, 2021 12:17 PM
To: Bonate, Peter <[email protected]>; Leonid Gibiansky
<[email protected]>; Niurys.CS <[email protected]>
Cc: [email protected]
Subject: RE: [NMusers] Assessment of elimination half life of mAb
Hi Pete,
I agree that it is hard to communicate. I like the general idea of C90 you
propose. I tend to choose something in between your and Leonid's answer, when
possible. I target an answer of "when is the pharmacodynamic effect <5% of the
maximum or therapeutic effect". It does require more than just the PK, though.
And for the just PK answer, I agree with Leonid and you, targeting some
smallish fraction of Cmax is often reasonable for similar communication.
What I find clinicians typically try to understand when the drug has washed
out. The answer that many have reasonably latched onto is when 5 half-lives
have passed, the drug is washed out. That suggests that about 3% (2^-5) effect
is generally agreed as being washed out.
To Niurys's question about a citation for this, I don't have one either.
It's just a rule-of-thumb that I have tended to use.
Thanks,
Bill
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Bonate, Peter
Sent: Thursday, April 29, 2021 12:01 PM
To: Leonid Gibiansky <[email protected]>; Niurys.CS
<[email protected]>
Cc: [email protected]
Subject: RE: [NMusers] Assessment of elimination half life of mAb
I've never really been happy with this. It's an unsatisfactory solution.
You have a nonlinear drug. Let's assume you have an approved drug. It's given
at some fixed dose. The clinician wants to know what is the drug's half-life
so they can washout their patient and start them on some other therapy. We go
back to them and say, we can't give you a half-life because it's a nonlinear
drug, but once the kinetics become linear the half-life is X hours. That is a
terrible answer. Maybe we need to come up with a new term, call it C90, the
time it takes for Cmax to decline by 90%. That we can do. We don't even need
an analytical solution, we can eyeball it. We could even get fancy and do it
in a population model. C90 - the time it takes for Cmax to decline 90% in 90%
of patients. Of course, for nonlinear drugs, C90 only holds for that dose.
Change in dose results in a new C90.
Just a thought.
pete
Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical Pharmacology and
Exploratory Development (CPED) Astellas
1 Astellas Way, N3.158
Northbrook, IL 60062
[email protected]
(224) 619-4901
It’s been a while since I’ve had something here, but here is a Dad joke.
Question: Do you know why the math book was sad?
Answer: Because it had so many problems
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Leonid Gibiansky
Sent: Thursday, April 29, 2021 9:54 AM
To: Niurys.CS <[email protected]>
Cc: [email protected]
Subject: Re: [NMusers] Assessment of elimination half life of mAb
I am not aware of any papers specifically addressing the half-live issue, but
there are tons of original papers and tutorials on TMDD, just search the web
Thanks Leonid
On 4/29/2021 9:48 AM, Niurys.CS wrote:
> Dear Leonid,
>
> Many thanks for clearing up my doubt. Can you suggest me any paper to
> go into this topic in any depth.
> Best,
> Niurys
>
> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
> <mailto:[email protected]>> escribió:
>
> There is no such thing as half-life of elimination for the nonlinear
> drug. But one can compute something like half-life:
>
> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
> defines the half-life at high doses/high concentrations when
> nonlinear elimination is saturated.
>
> 2. Washout time: for the linear drug, 5 half-lives can be used to
> define washout time. During this time, concentrations drop
> approximately 2^5=32 times. So one can simulate the desired dosing
> (single dose or steady state), find the time from Cmax to Cmax/32
> and call it washout time (or time to Cmax/64 to be conservative)
>
> Thanks
> Leonid
>
>
> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>
> Dear all
> I need some help to assess the elimination half life of a
> monoclonal antibody.
> The model that describes the data is a QSS aproximation of TMDD
> with Rmax constant. The model includes two binding process of
> mAb to its target: in central and peripheral compartments.
> Is there any specific equation to calcule lambda z and the
> elimination half life for each of the TMDD aproximations?
> Thanks
> Niurys
>
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Hi Bill, all,
I do much the same thing - when there's nonlinearity happening, I've found it
to be effective to plot concentration-time curves by doses and regimens of
interest and mark the times at which the (median?) clinically-defined threshold
for "washout" has been reached in each case. Of course this starts getting
unwieldy when there are lots of doses or regimens. A less attractive way would
be to produce a lookup table.
Sounds like everyone's thinking along the same lines...
Justin
Quoted reply history
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Bill Denney
Sent: Thursday, April 29, 2021 6:17 PM
To: Bonate, Peter <[email protected]>; Leonid Gibiansky
<[email protected]>; Niurys.CS <[email protected]>
Cc: [email protected]
Subject: RE: [NMusers] Assessment of elimination half life of mAb
Hi Pete,
I agree that it is hard to communicate. I like the general idea of C90 you
propose. I tend to choose something in between your and Leonid's answer, when
possible. I target an answer of "when is the pharmacodynamic effect <5% of the
maximum or therapeutic effect". It does require more than just the PK, though.
And for the just PK answer, I agree with Leonid and you, targeting some
smallish fraction of Cmax is often reasonable for similar communication.
What I find clinicians typically try to understand when the drug has washed
out. The answer that many have reasonably latched onto is when 5 half-lives
have passed, the drug is washed out. That suggests that about 3% (2^-5) effect
is generally agreed as being washed out.
To Niurys's question about a citation for this, I don't have one either.
It's just a rule-of-thumb that I have tended to use.
Thanks,
Bill
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Bonate, Peter
Sent: Thursday, April 29, 2021 12:01 PM
To: Leonid Gibiansky <[email protected]>; Niurys.CS
<[email protected]>
Cc: [email protected]
Subject: RE: [NMusers] Assessment of elimination half life of mAb
I've never really been happy with this. It's an unsatisfactory solution.
You have a nonlinear drug. Let's assume you have an approved drug. It's given
at some fixed dose. The clinician wants to know what is the drug's half-life
so they can washout their patient and start them on some other therapy. We go
back to them and say, we can't give you a half-life because it's a nonlinear
drug, but once the kinetics become linear the half-life is X hours. That is a
terrible answer. Maybe we need to come up with a new term, call it C90, the
time it takes for Cmax to decline by 90%. That we can do. We don't even need
an analytical solution, we can eyeball it. We could even get fancy and do it
in a population model. C90 - the time it takes for Cmax to decline 90% in 90%
of patients. Of course, for nonlinear drugs, C90 only holds for that dose.
Change in dose results in a new C90.
Just a thought.
pete
Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical Pharmacology and
Exploratory Development (CPED) Astellas
1 Astellas Way, N3.158
Northbrook, IL 60062
[email protected]
(224) 619-4901
It’s been a while since I’ve had something here, but here is a Dad joke.
Question: Do you know why the math book was sad?
Answer: Because it had so many problems
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Leonid Gibiansky
Sent: Thursday, April 29, 2021 9:54 AM
To: Niurys.CS <[email protected]>
Cc: [email protected]
Subject: Re: [NMusers] Assessment of elimination half life of mAb
I am not aware of any papers specifically addressing the half-live issue, but
there are tons of original papers and tutorials on TMDD, just search the web
Thanks Leonid
On 4/29/2021 9:48 AM, Niurys.CS wrote:
> Dear Leonid,
>
> Many thanks for clearing up my doubt. Can you suggest me any paper to
> go into this topic in any depth.
> Best,
> Niurys
>
> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
> <mailto:[email protected]>> escribió:
>
> There is no such thing as half-life of elimination for the nonlinear
> drug. But one can compute something like half-life:
>
> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
> defines the half-life at high doses/high concentrations when
> nonlinear elimination is saturated.
>
> 2. Washout time: for the linear drug, 5 half-lives can be used to
> define washout time. During this time, concentrations drop
> approximately 2^5=32 times. So one can simulate the desired dosing
> (single dose or steady state), find the time from Cmax to Cmax/32
> and call it washout time (or time to Cmax/64 to be conservative)
>
> Thanks
> Leonid
>
>
> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>
> Dear all
> I need some help to assess the elimination half life of a
> monoclonal antibody.
> The model that describes the data is a QSS aproximation of TMDD
> with Rmax constant. The model includes two binding process of
> mAb to its target: in central and peripheral compartments.
> Is there any specific equation to calcule lambda z and the
> elimination half life for each of the TMDD aproximations?
> Thanks
> Niurys
>
Hi Leonid,
First of all thanks for your response saying half-life has no useful meaning
for a drug with non-linear PK (clearance and/or volume, plasma protein binding,
etc).
Half-life is a useful parameter for some simple cases but when the question
about the time course of drug effect then half-life has little value. Add in
non-linear PK to the non-linear PD and then delayed concentration-effect makes
it even harder.
A simulation (a picture is worth a thousand words) can show the complexity and
also give a 'feeling' for the answer to the question. Pseudo-solutions like the
'context sensitive half-life' should be avoided because half-life only has a
scientifically useful meaning for first-order processes that can be visualised
as exponential curves.
Life is more than PK -- its PKPD is when it gets interesting (and complicated).
Best wishes,
Nick
--
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/
http://orcid.org/0000-0002-4031-2514
Read the question, answer the question, attempt all questions
Quoted reply history
-----Original Message-----
From: [email protected] <[email protected]> On Behalf Of
Leonid Gibiansky
Sent: Thursday, 29 April 2021 6:42 PM
To: Justin Wilkins <[email protected]>; Bill Denney
<[email protected]>; Bonate, Peter <[email protected]>;
Niurys.CS <[email protected]>
Cc: [email protected]
Subject: Re: [NMusers] Assessment of elimination half life of mAb
still, half-life of the linear part could be helpful in cases when
non-linearity plays no significant role in elimination, so we tend to present
it together with the washout time simulations.
Leonid
On 4/29/2021 12:35 PM, Justin Wilkins wrote:
> Hi Bill, all,
>
> I do much the same thing - when there's nonlinearity happening, I've found it
> to be effective to plot concentration-time curves by doses and regimens of
> interest and mark the times at which the (median?) clinically-defined
> threshold for "washout" has been reached in each case. Of course this starts
> getting unwieldy when there are lots of doses or regimens. A less attractive
> way would be to produce a lookup table.
>
> Sounds like everyone's thinking along the same lines...
>
> Justin
>
>
> -----Original Message-----
> From: [email protected] <[email protected]> On
> Behalf Of Bill Denney
> Sent: Thursday, April 29, 2021 6:17 PM
> To: Bonate, Peter <[email protected]>; Leonid Gibiansky
> <[email protected]>; Niurys.CS <[email protected]>
> Cc: [email protected]
> Subject: RE: [NMusers] Assessment of elimination half life of mAb
>
> Hi Pete,
>
> I agree that it is hard to communicate. I like the general idea of C90 you
> propose. I tend to choose something in between your and Leonid's answer,
> when possible. I target an answer of "when is the pharmacodynamic effect <5%
> of the maximum or therapeutic effect". It does require more than just the
> PK, though. And for the just PK answer, I agree with Leonid and you,
> targeting some smallish fraction of Cmax is often reasonable for similar
> communication.
>
> What I find clinicians typically try to understand when the drug has washed
> out. The answer that many have reasonably latched onto is when 5 half-lives
> have passed, the drug is washed out. That suggests that about 3% (2^-5)
> effect is generally agreed as being washed out.
>
> To Niurys's question about a citation for this, I don't have one either.
> It's just a rule-of-thumb that I have tended to use.
>
> Thanks,
>
> Bill
>
> -----Original Message-----
> From: [email protected] <[email protected]> On
> Behalf Of Bonate, Peter
> Sent: Thursday, April 29, 2021 12:01 PM
> To: Leonid Gibiansky <[email protected]>; Niurys.CS
> <[email protected]>
> Cc: [email protected]
> Subject: RE: [NMusers] Assessment of elimination half life of mAb
>
> I've never really been happy with this. It's an unsatisfactory solution.
> You have a nonlinear drug. Let's assume you have an approved drug. It's
> given at some fixed dose. The clinician wants to know what is the drug's
> half-life so they can washout their patient and start them on some other
> therapy. We go back to them and say, we can't give you a half-life because
> it's a nonlinear drug, but once the kinetics become linear the half-life is X
> hours. That is a terrible answer. Maybe we need to come up with a new term,
> call it C90, the time it takes for Cmax to decline by 90%. That we can do.
> We don't even need an analytical solution, we can eyeball it. We could even
> get fancy and do it in a population model. C90 - the time it takes for Cmax
> to decline 90% in 90% of patients. Of course, for nonlinear drugs, C90 only
> holds for that dose. Change in dose results in a new C90.
> Just a thought.
>
> pete
>
>
>
> Peter Bonate, PhD
> Executive Director
> Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical
> Pharmacology and Exploratory Development (CPED) Astellas
> 1 Astellas Way, N3.158
> Northbrook, IL 60062
> [email protected]
> (224) 619-4901
>
>
> It’s been a while since I’ve had something here, but here is a Dad joke.
>
> Question: Do you know why the math book was sad?
> Answer: Because it had so many problems
>
>
> -----Original Message-----
> From: [email protected] <[email protected]> On
> Behalf Of Leonid Gibiansky
> Sent: Thursday, April 29, 2021 9:54 AM
> To: Niurys.CS <[email protected]>
> Cc: [email protected]
> Subject: Re: [NMusers] Assessment of elimination half life of mAb
>
> I am not aware of any papers specifically addressing the half-live
> issue, but there are tons of original papers and tutorials on TMDD,
> just search the web Thanks Leonid
>
> On 4/29/2021 9:48 AM, Niurys.CS wrote:
>> Dear Leonid,
>>
>> Many thanks for clearing up my doubt. Can you suggest me any paper to
>> go into this topic in any depth.
>> Best,
>> Niurys
>>
>> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
>> <mailto:[email protected]>> escribió:
>>
>> There is no such thing as half-life of elimination for the nonlinear
>> drug. But one can compute something like half-life:
>>
>> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
>> defines the half-life at high doses/high concentrations when
>> nonlinear elimination is saturated.
>>
>> 2. Washout time: for the linear drug, 5 half-lives can be used to
>> define washout time. During this time, concentrations drop
>> approximately 2^5=32 times. So one can simulate the desired dosing
>> (single dose or steady state), find the time from Cmax to Cmax/32
>> and call it washout time (or time to Cmax/64 to be conservative)
>>
>> Thanks
>> Leonid
>>
>>
>> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>>
>> Dear all
>> I need some help to assess the elimination half life of a
>> monoclonal antibody.
>> The model that describes the data is a QSS aproximation of TMDD
>> with Rmax constant. The model includes two binding process of
>> mAb to its target: in central and peripheral compartments.
>> Is there any specific equation to calcule lambda z and the
>> elimination half life for each of the TMDD aproximations?
>> Thanks
>> Niurys
>>
>
A simulation like https://www.boomer.org/c/p4/js/w200101/index1.php
For example use Dose = 500, V1 = 25, Vm = 200 and Km = 5, Max X = 148 and
semi-log. Compare with Vm = 160 and Km = 4. Same terminal slope, t(1/2)
approximately 10 hr.
BTW, NCA isn’t very good for non linear PK. Not sure that PopPK helps much. The
low concentration k and this t(1/2) could be estimated from Vm and Km but not
much help at higher concentrations.
Some equations on https://www.boomer.org/c/p4/c21/c2103.php especially 21.3.3,
21.3.4 and 21.3.5.
For a ’simple’ iv bolus simulation you need Dose, V1, Vm, and Km estimates.
Distribution parameters for multi-compartment. Absorption parameters for oral.
David Bourne
PS, I have a vague memory of a patient with phenytoin concentration dropping
from 25 to 24 mg/L over 24 hours. Low concentration t(1/2) might be 12 hr. TDM
anyone ;-)
db
Quoted reply history
> On Apr 29, 2021, at 11:34 AM, Niurys.CS <[email protected]> wrote:
>
> Dear all,
>
> I'm very grateful for these ideas and explanations. Actually, I was worry
> about this topic. Previously, I reported the values of half life by NCA;
> however the clinicians are asking for a half life value estimated by
> population PK.
> Many thanks to you in the name of Cuban team.
> Niurys
>
> El 29/04/2021 12:49, "Bonate, Peter" <[email protected]> escribió:
> All I can say is, Great minds.....
>
> Maybe some of these ideas can help you, Niurys.
>
> pete
>
>
>
> Peter Bonate, PhD
> Executive Director
> Pharmacokinetics, Modeling, and Simulation (PKMS)
> Clinical Pharmacology and Exploratory Development (CPED)
> Astellas
> 1 Astellas Way, N3.158
> Northbrook, IL 60062
> [email protected]
> (224) 619-4901
>
>
> It’s been a while since I’ve had something here, but here is a Dad joke.
>
> Question: Do you know why the math book was sad?
> Answer: Because it had so many problems
>
>
> -----Original Message-----
> From: Leonid Gibiansky <[email protected]>
> Sent: Thursday, April 29, 2021 11:42 AM
> To: Justin Wilkins <[email protected]>; Bill Denney
> <[email protected]>; Bonate, Peter <[email protected]>;
> Niurys.CS <[email protected]>
> Cc: [email protected]
> Subject: Re: [NMusers] Assessment of elimination half life of mAb
>
> still, half-life of the linear part could be helpful in cases when
> non-linearity plays no significant role in elimination, so we tend to present
> it together with the washout time simulations.
>
> Leonid
>
>
>
> On 4/29/2021 12:35 PM, Justin Wilkins wrote:
> > Hi Bill, all,
> >
> > I do much the same thing - when there's nonlinearity happening, I've found
> > it to be effective to plot concentration-time curves by doses and regimens
> > of interest and mark the times at which the (median?) clinically-defined
> > threshold for "washout" has been reached in each case. Of course this
> > starts getting unwieldy when there are lots of doses or regimens. A less
> > attractive way would be to produce a lookup table.
> >
> > Sounds like everyone's thinking along the same lines...
> >
> > Justin
> >
> >
> > -----Original Message-----
> > From: [email protected] <[email protected]> On
> > Behalf Of Bill Denney
> > Sent: Thursday, April 29, 2021 6:17 PM
> > To: Bonate, Peter <[email protected]>; Leonid Gibiansky
> > <[email protected]>; Niurys.CS <[email protected]>
> > Cc: [email protected]
> > Subject: RE: [NMusers] Assessment of elimination half life of mAb
> >
> > Hi Pete,
> >
> > I agree that it is hard to communicate. I like the general idea of C90 you
> > propose. I tend to choose something in between your and Leonid's answer,
> > when possible. I target an answer of "when is the pharmacodynamic effect
> > <5% of the maximum or therapeutic effect". It does require more than just
> > the PK, though. And for the just PK answer, I agree with Leonid and you,
> > targeting some smallish fraction of Cmax is often reasonable for similar
> > communication.
> >
> > What I find clinicians typically try to understand when the drug has washed
> > out. The answer that many have reasonably latched onto is when 5
> > half-lives have passed, the drug is washed out. That suggests that about
> > 3% (2^-5) effect is generally agreed as being washed out.
> >
> > To Niurys's question about a citation for this, I don't have one either.
> > It's just a rule-of-thumb that I have tended to use.
> >
> > Thanks,
> >
> > Bill
> >
> > -----Original Message-----
> > From: [email protected] <[email protected]> On
> > Behalf Of Bonate, Peter
> > Sent: Thursday, April 29, 2021 12:01 PM
> > To: Leonid Gibiansky <[email protected]>; Niurys.CS
> > <[email protected]>
> > Cc: [email protected]
> > Subject: RE: [NMusers] Assessment of elimination half life of mAb
> >
> > I've never really been happy with this. It's an unsatisfactory solution.
> > You have a nonlinear drug. Let's assume you have an approved drug. It's
> > given at some fixed dose. The clinician wants to know what is the drug's
> > half-life so they can washout their patient and start them on some other
> > therapy. We go back to them and say, we can't give you a half-life because
> > it's a nonlinear drug, but once the kinetics become linear the half-life is
> > X hours. That is a terrible answer. Maybe we need to come up with a new
> > term, call it C90, the time it takes for Cmax to decline by 90%. That we
> > can do. We don't even need an analytical solution, we can eyeball it. We
> > could even get fancy and do it in a population model. C90 - the time it
> > takes for Cmax to decline 90% in 90% of patients. Of course, for nonlinear
> > drugs, C90 only holds for that dose. Change in dose results in a new C90.
> > Just a thought.
> >
> > pete
> >
> >
> >
> > Peter Bonate, PhD
> > Executive Director
> > Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical
> > Pharmacology and Exploratory Development (CPED) Astellas
> > 1 Astellas Way, N3.158
> > Northbrook, IL 60062
> > [email protected]
> > (224) 619-4901
> >
> >
> > It’s been a while since I’ve had something here, but here is a Dad joke.
> >
> > Question: Do you know why the math book was sad?
> > Answer: Because it had so many problems
> >
> >
> > -----Original Message-----
> > From: [email protected] <[email protected]> On
> > Behalf Of Leonid Gibiansky
> > Sent: Thursday, April 29, 2021 9:54 AM
> > To: Niurys.CS <[email protected]>
> > Cc: [email protected]
> > Subject: Re: [NMusers] Assessment of elimination half life of mAb
> >
> > I am not aware of any papers specifically addressing the half-live
> > issue, but there are tons of original papers and tutorials on TMDD,
> > just search the web Thanks Leonid
> >
> > On 4/29/2021 9:48 AM, Niurys.CS wrote:
> >> Dear Leonid,
> >>
> >> Many thanks for clearing up my doubt. Can you suggest me any paper to
> >> go into this topic in any depth.
> >> Best,
> >> Niurys
> >>
> >> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
> >> <mailto:[email protected]>> escribió:
> >>
> >> There is no such thing as half-life of elimination for the nonlinear
> >> drug. But one can compute something like half-life:
> >>
> >> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
> >> defines the half-life at high doses/high concentrations when
> >> nonlinear elimination is saturated.
> >>
> >> 2. Washout time: for the linear drug, 5 half-lives can be used to
> >> define washout time. During this time, concentrations drop
> >> approximately 2^5=32 times. So one can simulate the desired dosing
> >> (single dose or steady state), find the time from Cmax to Cmax/32
> >> and call it washout time (or time to Cmax/64 to be conservative)
> >>
> >> Thanks
> >> Leonid
> >>
> >>
> >> On 4/28/2021 5:17 PM, Niurys.CS wrote:
> >>
> >> Dear all
> >> I need some help to assess the elimination half life of a
> >> monoclonal antibody.
> >> The model that describes the data is a QSS aproximation of TMDD
> >> with Rmax constant. The model includes two binding process of
> >> mAb to its target: in central and peripheral compartments.
> >> Is there any specific equation to calcule lambda z and the
> >> elimination half life for each of the TMDD aproximations?
> >> Thanks
> >> Niurys
> >>
> >
Half-life is more relevant for first-order kinetics. For nonlinear PK,
half-life changes with concentration (~dose) and thus is not useful. As
David pointed out, phenytoin is a good example for this. We use the
Michaelis-Menten (MM) equation for dose calculations in case of phenytoin.
In that, a t90% equation derived from MM is used to calculate time to reach
90% steady-state at a given dose using Vmax,Km, Volume of distribution and
Dose. Here is a book chapter that may be useful for basic understanding on
nonlinear PK.
Concepts in Clinical Pharmacokinetics. Southwood, Fleming and Huckaby. 7th Ed.
American Society of Health-System PharmacistsASHP eBooks (digital.ashp.org).
Lesson 10: Nonlinear processes.
Regards,
Ayyappa
Quoted reply history
On Thu, Apr 29, 2021 at 1:11 PM David at Booomer <[email protected]> wrote:
> A simulation like https://www.boomer.org/c/p4/js/w200101/index1.php
> For example use Dose = 500, V1 = 25, Vm = 200 and Km = 5, Max X = 148 and
> semi-log. Compare with Vm = 160 and Km = 4. Same terminal slope, t(1/2)
> approximately 10 hr.
>
> BTW, NCA isn’t very good for non linear PK. Not sure that PopPK helps
> much. The low concentration k and this t(1/2) could be estimated from Vm
> and Km but not much help at higher concentrations.
>
> Some equations on https://www.boomer.org/c/p4/c21/c2103.php especially
> 21.3.3, 21.3.4 and 21.3.5.
>
> For a ’simple’ iv bolus simulation you need Dose, V1, Vm, and Km
> estimates. Distribution parameters for multi-compartment. Absorption
> parameters for oral.
>
> David Bourne
>
> PS, I have a vague memory of a patient with phenytoin concentration
> dropping from 25 to 24 mg/L over 24 hours. Low concentration t(1/2) might
> be 12 hr. TDM anyone ;-)
>
> db
>
> > On Apr 29, 2021, at 11:34 AM, Niurys.CS <[email protected]> wrote:
> >
> > Dear all,
> >
> > I'm very grateful for these ideas and explanations. Actually, I was
> worry about this topic. Previously, I reported the values of half life by
> NCA; however the clinicians are asking for a half life value estimated by
> population PK.
> > Many thanks to you in the name of Cuban team.
> > Niurys
> >
> > El 29/04/2021 12:49, "Bonate, Peter" <[email protected]>
> escribió:
> > All I can say is, Great minds.....
> >
> > Maybe some of these ideas can help you, Niurys.
> >
> > pete
> >
> >
> >
> > Peter Bonate, PhD
> > Executive Director
> > Pharmacokinetics, Modeling, and Simulation (PKMS)
> > Clinical Pharmacology and Exploratory Development (CPED)
> > Astellas
> > 1 Astellas Way, N3.158
> > Northbrook, IL 60062
> > [email protected]
> > (224) 619-4901
> >
> >
> > It’s been a while since I’ve had something here, but here is a Dad joke.
> >
> > Question: Do you know why the math book was sad?
> > Answer: Because it had so many problems
> >
> >
> > -----Original Message-----
> > From: Leonid Gibiansky <[email protected]>
> > Sent: Thursday, April 29, 2021 11:42 AM
> > To: Justin Wilkins <[email protected]>; Bill Denney <
> [email protected]>; Bonate, Peter <[email protected]>;
> Niurys.CS <[email protected]>
> > Cc: [email protected]
> > Subject: Re: [NMusers] Assessment of elimination half life of mAb
> >
> > still, half-life of the linear part could be helpful in cases when
> non-linearity plays no significant role in elimination, so we tend to
> present it together with the washout time simulations.
> >
> > Leonid
> >
> >
> >
> > On 4/29/2021 12:35 PM, Justin Wilkins wrote:
> > > Hi Bill, all,
> > >
> > > I do much the same thing - when there's nonlinearity happening, I've
> found it to be effective to plot concentration-time curves by doses and
> regimens of interest and mark the times at which the (median?)
> clinically-defined threshold for "washout" has been reached in each case.
> Of course this starts getting unwieldy when there are lots of doses or
> regimens. A less attractive way would be to produce a lookup table.
> > >
> > > Sounds like everyone's thinking along the same lines...
> > >
> > > Justin
> > >
> > >
> > > -----Original Message-----
> > > From: [email protected] <[email protected]> On
> > > Behalf Of Bill Denney
> > > Sent: Thursday, April 29, 2021 6:17 PM
> > > To: Bonate, Peter <[email protected]>; Leonid Gibiansky
> > > <[email protected]>; Niurys.CS <[email protected]>
> > > Cc: [email protected]
> > > Subject: RE: [NMusers] Assessment of elimination half life of mAb
> > >
> > > Hi Pete,
> > >
> > > I agree that it is hard to communicate. I like the general idea of
> C90 you propose. I tend to choose something in between your and Leonid's
> answer, when possible. I target an answer of "when is the pharmacodynamic
> effect <5% of the maximum or therapeutic effect". It does require more
> than just the PK, though. And for the just PK answer, I agree with Leonid
> and you, targeting some smallish fraction of Cmax is often reasonable for
> similar communication.
> > >
> > > What I find clinicians typically try to understand when the drug has
> washed out. The answer that many have reasonably latched onto is when 5
> half-lives have passed, the drug is washed out. That suggests that about
> 3% (2^-5) effect is generally agreed as being washed out.
> > >
> > > To Niurys's question about a citation for this, I don't have one
> either.
> > > It's just a rule-of-thumb that I have tended to use.
> > >
> > > Thanks,
> > >
> > > Bill
> > >
> > > -----Original Message-----
> > > From: [email protected] <[email protected]> On
> > > Behalf Of Bonate, Peter
> > > Sent: Thursday, April 29, 2021 12:01 PM
> > > To: Leonid Gibiansky <[email protected]>; Niurys.CS
> > > <[email protected]>
> > > Cc: [email protected]
> > > Subject: RE: [NMusers] Assessment of elimination half life of mAb
> > >
> > > I've never really been happy with this. It's an unsatisfactory
> solution.
> > > You have a nonlinear drug. Let's assume you have an approved drug.
> It's given at some fixed dose. The clinician wants to know what is the
> drug's half-life so they can washout their patient and start them on some
> other therapy. We go back to them and say, we can't give you a half-life
> because it's a nonlinear drug, but once the kinetics become linear the
> half-life is X hours. That is a terrible answer. Maybe we need to come up
> with a new term, call it C90, the time it takes for Cmax to decline by
> 90%. That we can do. We don't even need an analytical solution, we can
> eyeball it. We could even get fancy and do it in a population model. C90
> - the time it takes for Cmax to decline 90% in 90% of patients. Of course,
> for nonlinear drugs, C90 only holds for that dose. Change in dose results
> in a new C90.
> > > Just a thought.
> > >
> > > pete
> > >
> > >
> > >
> > > Peter Bonate, PhD
> > > Executive Director
> > > Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical
> > > Pharmacology and Exploratory Development (CPED) Astellas
> > > 1 Astellas Way, N3.158
> > > Northbrook, IL 60062
> > > [email protected]
> > > (224) 619-4901
> > >
> > >
> > > It’s been a while since I’ve had something here, but here is a Dad
> joke.
> > >
> > > Question: Do you know why the math book was sad?
> > > Answer: Because it had so many problems
> > >
> > >
> > > -----Original Message-----
> > > From: [email protected] <[email protected]> On
> > > Behalf Of Leonid Gibiansky
> > > Sent: Thursday, April 29, 2021 9:54 AM
> > > To: Niurys.CS <[email protected]>
> > > Cc: [email protected]
> > > Subject: Re: [NMusers] Assessment of elimination half life of mAb
> > >
> > > I am not aware of any papers specifically addressing the half-live
> > > issue, but there are tons of original papers and tutorials on TMDD,
> > > just search the web Thanks Leonid
> > >
> > > On 4/29/2021 9:48 AM, Niurys.CS wrote:
> > >> Dear Leonid,
> > >>
> > >> Many thanks for clearing up my doubt. Can you suggest me any paper to
> > >> go into this topic in any depth.
> > >> Best,
> > >> Niurys
> > >>
> > >> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
> > >> <mailto:[email protected]>> escribió:
> > >>
> > >> There is no such thing as half-life of elimination for the
> nonlinear
> > >> drug. But one can compute something like half-life:
> > >>
> > >> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
> > >> defines the half-life at high doses/high concentrations when
> > >> nonlinear elimination is saturated.
> > >>
> > >> 2. Washout time: for the linear drug, 5 half-lives can be used to
> > >> define washout time. During this time, concentrations drop
> > >> approximately 2^5=32 times. So one can simulate the desired
> dosing
> > >> (single dose or steady state), find the time from Cmax to Cmax/32
> > >> and call it washout time (or time to Cmax/64 to be conservative)
> > >>
> > >> Thanks
> > >> Leonid
> > >>
> > >>
> > >> On 4/28/2021 5:17 PM, Niurys.CS wrote:
> > >>
> > >> Dear all
> > >> I need some help to assess the elimination half life of a
> > >> monoclonal antibody.
> > >> The model that describes the data is a QSS aproximation of
> TMDD
> > >> with Rmax constant. The model includes two binding process of
> > >> mAb to its target: in central and peripheral compartments.
> > >> Is there any specific equation to calcule lambda z and the
> > >> elimination half life for each of the TMDD aproximations?
> > >> Thanks
> > >> Niurys
> > >>
> > >
>
>
>
Dear all,
I personaly believe that using log-linear half-life calculated using the biggest dose is the best (if not the "least worst") solution, even if it cannot be pretended to be a beta-T1/2.
Indeed, deriving beta-T1/2 using linear PK parameters (V, CL,...) obtained from a nonlinear PK model (Quasi-steady-state, Michaelis-Menten, etc) may lead to surprising parameters.
Let us take as an example anti-PCSK9 mAbs, evolocumab and alirocumab. Using the strategy consisting of the use of linear PK parameters, beta-1/2 were :
Evolocumab : beta-T/2 = 7.2 days (Gibbs, 2016) vs. 34 days (Kuchimanchi, 2018)
Alirocumab : beta-T1/2 = 29 days (Djebli, 2018) vs. 13 days (Martinez, 2018)
Therefore, an apparently nice nonlinear PK model does not imply a good "separation" of linear and nonlinear parts, leading to possible misspecification of linear elimination.
In addition, the interpretation of linear elimination is what is observed in absence of antigen mass, and thus questions its relevance.
Best regards,
David
----- Mail original -----
Quoted reply history
De: "Saeheum Song" <ss.pkpdmodel
À: "Niurys.CS" <amaranthfan
Cc: "Peter Bonate" <Peter.Bonate
npredictions.com>, "Justin Wilkins" <justin.wilkins
obomaxnm.com, "Leonid Gibiansky" <lgibiansky
Envoyé: Vendredi 30 Avril 2021 10:53:44
Objet: Re: [NMusers] Assessment of elimination half life of mAb
I would report maximum half life, where system is saturated with additional statement of shorter when system is unsaturated.
This will satisfy clinicians queries, I believe
On Thu, Apr 29, 2021, 1:46 PM Niurys.CS < amaranthfan
Dear all,
I'm very grateful for these ideas and explanations. Actually, I was worry about this topic. Previously, I reported the values of half life by NCA; however the clinicians are asking for a half life value estimated by population PK.
Many thanks to you in the name of Cuban team.
Niurys
El 29/04/2021 12:49, "Bonate, Peter" < Peter.Bonate
ó:
All I can say is, Great minds.....
Maybe some of these ideas can help you, Niurys.
pete
Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS)
Clinical Pharmacology and Exploratory Development (CPED)
Astellas
1 Astellas Way, N3.158
Northbrook, IL 60062
Peter.bonate
(224) 619-4901
It’s been a while since I’ve had something here, but here is a Dad joke.
Question: Do you know why the math book was sad?
Answer: Because it had so many problems
-----Original Message-----
From: Leonid Gibiansky < lgibiansky
Sent: Thursday, April 29, 2021 11:42 AM
To: Justin Wilkins < justin.wilkins
anpredictions.com >; Bonate, Peter < Peter.Bonate
< amaranthfan
Cc: nmusers
Subject: Re: [NMusers] Assessment of elimination half life of mAb
still, half-life of the linear part could be helpful in cases when non-linearity plays no significant role in elimination, so we tend to present it together with the washout time simulations.
Leonid
On 4/29/2021 12:35 PM, Justin Wilkins wrote:
> Hi Bill, all,
>
> I do much the same thing - when there's nonlinearity happening, I've foun
d it to be effective to plot concentration-time curves by doses and regimens of interest and mark the times at which the (median?) clinically-defined threshold for "washout" has been reached in each case. Of course this starts getting unwieldy when there are lots of doses or regimens. A less attractive way would be to produce a lookup table.
>
> Sounds like everyone's thinking along the same lines...
>
> Justin
>
>
> -----Original Message-----
> From: owner-nmusers
> Behalf Of Bill Denney
> Sent: Thursday, April 29, 2021 6:17 PM
> To: Bonate, Peter < Peter.Bonate
> < lgibiansky
> Cc: nmusers
> Subject: RE: [NMusers] Assessment of elimination half life of mAb
>
> Hi Pete,
>
> I agree that it is hard to communicate. I like the general idea of C90 yo
u propose. I tend to choose something in between your and Leonid's answer, when possible. I target an answer of "when is the pharmacodynamic effect <5% of the maximum or therapeutic effect". It does require more than just the PK, though. And for the just PK answer, I agree with Leonid and you, targeting some smallish fraction of Cmax is often reasonable for similar communication.
>
> What I find clinicians typically try to understand when the drug has wash
ed out. The answer that many have reasonably latched onto is when 5 half-lives have passed, the drug is washed out. That suggests that about 3% (2^-5) effect is generally agreed as being washed out.
>
> To Niurys's question about a citation for this, I don't have one either.
> It's just a rule-of-thumb that I have tended to use.
>
> Thanks,
>
> Bill
>
> -----Original Message-----
> From: owner-nmusers
> Behalf Of Bonate, Peter
> Sent: Thursday, April 29, 2021 12:01 PM
> To: Leonid Gibiansky < lgibiansky
> < amaranthfan
> Cc: nmusers
> Subject: RE: [NMusers] Assessment of elimination half life of mAb
>
> I've never really been happy with this. It's an unsatisfactory solution.
> You have a nonlinear drug. Let's assume you have an approved drug. It's g
iven at some fixed dose. The clinician wants to know what is the drug's half-life so they can washout their patient and start them on some other therapy. We go back to them and say, we can't give you a half-life because it's a nonlinear drug, but once the kinetics become linear the half-life is X hours. That is a terrible answer. Maybe we need to come up with a new term, call it C90, the time it takes for Cmax to decline by 90%. That we can do. We don't even need an analytical solution, we can eyeball it. We could even get fancy and do it in a population model. C90 - the time it takes for Cmax to decline 90% in 90% of patients. Of course, for nonlinear drugs, C90 only holds for that dose. Change in dose results in a new C90.
> Just a thought.
>
> pete
>
>
>
> Peter Bonate, PhD
> Executive Director
> Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical
> Pharmacology and Exploratory Development (CPED) Astellas
> 1 Astellas Way, N3.158
> Northbrook, IL 60062
> Peter.bonate
> (224) 619-4901
>
>
> It’s been a while since I’ve had something here, but here
is a Dad joke.
>
> Question: Do you know why the math book was sad?
> Answer: Because it had so many problems
>
>
> -----Original Message-----
> From: owner-nmusers
> Behalf Of Leonid Gibiansky
> Sent: Thursday, April 29, 2021 9:54 AM
> To: Niurys.CS < amaranthfan
> Cc: nmusers
> Subject: Re: [NMusers] Assessment of elimination half life of mAb
>
> I am not aware of any papers specifically addressing the half-live
> issue, but there are tons of original papers and tutorials on TMDD,
> just search the web Thanks Leonid
>
> On 4/29/2021 9:48 AM, Niurys.CS wrote:
>> Dear Leonid,
>>
>> Many thanks for clearing up my doubt. Can you suggest me any paper to
>> go into this topic in any depth.
>> Best,
>> Niurys
>>
>> El 28/04/2021 19:34, "Leonid Gibiansky" < lgibiansky
>> <mailto: lgibiansky
>>
>> There is no such thing as half-life of elimination for the nonlinear
>> drug. But one can compute something like half-life:
>>
>> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
>> defines the half-life at high doses/high concentrations when
>> nonlinear elimination is saturated.
>>
>> 2. Washout time: for the linear drug, 5 half-lives can be used to
>> define washout time. During this time, concentrations drop
>> approximately 2^52 times. So one can simulate the desired dosing
>> (single dose or steady state), find the time from Cmax to Cmax/32
>> and call it washout time (or time to Cmax/64 to be conservative)
>>
>> Thanks
>> Leonid
>>
>>
>> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>>
>> Dear all
>> I need some help to assess the elimination half life of a
>> monoclonal antibody.
>> The model that describes the data is a QSS aproximation of TMDD
>> with Rmax constant. The model includes two binding process of
>> mAb to its target: in central and peripheral compartments.
>> Is there any specific equation to calcule lambda z and the
>> elimination half life for each of the TMDD aproximations?
>> Thanks
>> Niurys
>>
>
I would report maximum half life, where system is saturated with additional
statement of shorter when system is unsaturated.
This will satisfy clinicians queries, I believe
Quoted reply history
On Thu, Apr 29, 2021, 1:46 PM Niurys.CS <[email protected]> wrote:
> Dear all,
>
> I'm very grateful for these ideas and explanations. Actually, I was worry
> about this topic. Previously, I reported the values of half life by NCA;
> however the clinicians are asking for a half life value estimated by
> population PK.
> Many thanks to you in the name of Cuban team.
> Niurys
> El 29/04/2021 12:49, "Bonate, Peter" <[email protected]> escribió:
>
>> All I can say is, Great minds.....
>>
>> Maybe some of these ideas can help you, Niurys.
>>
>> pete
>>
>>
>>
>> Peter Bonate, PhD
>> Executive Director
>> Pharmacokinetics, Modeling, and Simulation (PKMS)
>> Clinical Pharmacology and Exploratory Development (CPED)
>> Astellas
>> 1 Astellas Way, N3.158
>> Northbrook, IL 60062
>> [email protected]
>> (224) 619-4901
>>
>>
>> It’s been a while since I’ve had something here, but here is a Dad joke.
>>
>> Question: Do you know why the math book was sad?
>> Answer: Because it had so many problems
>>
>>
>> -----Original Message-----
>> From: Leonid Gibiansky <[email protected]>
>> Sent: Thursday, April 29, 2021 11:42 AM
>> To: Justin Wilkins <[email protected]>; Bill Denney <
>> [email protected]>; Bonate, Peter <[email protected]>;
>> Niurys.CS <[email protected]>
>> Cc: [email protected]
>> Subject: Re: [NMusers] Assessment of elimination half life of mAb
>>
>> still, half-life of the linear part could be helpful in cases when
>> non-linearity plays no significant role in elimination, so we tend to
>> present it together with the washout time simulations.
>>
>> Leonid
>>
>>
>>
>> On 4/29/2021 12:35 PM, Justin Wilkins wrote:
>> > Hi Bill, all,
>> >
>> > I do much the same thing - when there's nonlinearity happening, I've
>> found it to be effective to plot concentration-time curves by doses and
>> regimens of interest and mark the times at which the (median?)
>> clinically-defined threshold for "washout" has been reached in each case.
>> Of course this starts getting unwieldy when there are lots of doses or
>> regimens. A less attractive way would be to produce a lookup table.
>> >
>> > Sounds like everyone's thinking along the same lines...
>> >
>> > Justin
>> >
>> >
>> > -----Original Message-----
>> > From: [email protected] <[email protected]> On
>> > Behalf Of Bill Denney
>> > Sent: Thursday, April 29, 2021 6:17 PM
>> > To: Bonate, Peter <[email protected]>; Leonid Gibiansky
>> > <[email protected]>; Niurys.CS <[email protected]>
>> > Cc: [email protected]
>> > Subject: RE: [NMusers] Assessment of elimination half life of mAb
>> >
>> > Hi Pete,
>> >
>> > I agree that it is hard to communicate. I like the general idea of C90
>> you propose. I tend to choose something in between your and Leonid's
>> answer, when possible. I target an answer of "when is the pharmacodynamic
>> effect <5% of the maximum or therapeutic effect". It does require more
>> than just the PK, though. And for the just PK answer, I agree with Leonid
>> and you, targeting some smallish fraction of Cmax is often reasonable for
>> similar communication.
>> >
>> > What I find clinicians typically try to understand when the drug has
>> washed out. The answer that many have reasonably latched onto is when 5
>> half-lives have passed, the drug is washed out. That suggests that about
>> 3% (2^-5) effect is generally agreed as being washed out.
>> >
>> > To Niurys's question about a citation for this, I don't have one either.
>> > It's just a rule-of-thumb that I have tended to use.
>> >
>> > Thanks,
>> >
>> > Bill
>> >
>> > -----Original Message-----
>> > From: [email protected] <[email protected]> On
>> > Behalf Of Bonate, Peter
>> > Sent: Thursday, April 29, 2021 12:01 PM
>> > To: Leonid Gibiansky <[email protected]>; Niurys.CS
>> > <[email protected]>
>> > Cc: [email protected]
>> > Subject: RE: [NMusers] Assessment of elimination half life of mAb
>> >
>> > I've never really been happy with this. It's an unsatisfactory
>> solution.
>> > You have a nonlinear drug. Let's assume you have an approved drug.
>> It's given at some fixed dose. The clinician wants to know what is the
>> drug's half-life so they can washout their patient and start them on some
>> other therapy. We go back to them and say, we can't give you a half-life
>> because it's a nonlinear drug, but once the kinetics become linear the
>> half-life is X hours. That is a terrible answer. Maybe we need to come up
>> with a new term, call it C90, the time it takes for Cmax to decline by
>> 90%. That we can do. We don't even need an analytical solution, we can
>> eyeball it. We could even get fancy and do it in a population model. C90
>> - the time it takes for Cmax to decline 90% in 90% of patients. Of course,
>> for nonlinear drugs, C90 only holds for that dose. Change in dose results
>> in a new C90.
>> > Just a thought.
>> >
>> > pete
>> >
>> >
>> >
>> > Peter Bonate, PhD
>> > Executive Director
>> > Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical
>> > Pharmacology and Exploratory Development (CPED) Astellas
>> > 1 Astellas Way, N3.158
>> > Northbrook, IL 60062
>> > [email protected]
>> > (224) 619-4901
>> >
>> >
>> > It’s been a while since I’ve had something here, but here is a Dad joke.
>> >
>> > Question: Do you know why the math book was sad?
>> > Answer: Because it had so many problems
>> >
>> >
>> > -----Original Message-----
>> > From: [email protected] <[email protected]> On
>> > Behalf Of Leonid Gibiansky
>> > Sent: Thursday, April 29, 2021 9:54 AM
>> > To: Niurys.CS <[email protected]>
>> > Cc: [email protected]
>> > Subject: Re: [NMusers] Assessment of elimination half life of mAb
>> >
>> > I am not aware of any papers specifically addressing the half-live
>> > issue, but there are tons of original papers and tutorials on TMDD,
>> > just search the web Thanks Leonid
>> >
>> > On 4/29/2021 9:48 AM, Niurys.CS wrote:
>> >> Dear Leonid,
>> >>
>> >> Many thanks for clearing up my doubt. Can you suggest me any paper to
>> >> go into this topic in any depth.
>> >> Best,
>> >> Niurys
>> >>
>> >> El 28/04/2021 19:34, "Leonid Gibiansky" <[email protected]
>> >> <mailto:[email protected]>> escribió:
>> >>
>> >> There is no such thing as half-life of elimination for the
>> nonlinear
>> >> drug. But one can compute something like half-life:
>> >>
>> >> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
>> >> defines the half-life at high doses/high concentrations when
>> >> nonlinear elimination is saturated.
>> >>
>> >> 2. Washout time: for the linear drug, 5 half-lives can be used to
>> >> define washout time. During this time, concentrations drop
>> >> approximately 2^5=32 times. So one can simulate the desired dosing
>> >> (single dose or steady state), find the time from Cmax to Cmax/32
>> >> and call it washout time (or time to Cmax/64 to be conservative)
>> >>
>> >> Thanks
>> >> Leonid
>> >>
>> >>
>> >> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>> >>
>> >> Dear all
>> >> I need some help to assess the elimination half life of a
>> >> monoclonal antibody.
>> >> The model that describes the data is a QSS aproximation of
>> TMDD
>> >> with Rmax constant. The model includes two binding process of
>> >> mAb to its target: in central and peripheral compartments.
>> >> Is there any specific equation to calcule lambda z and the
>> >> elimination half life for each of the TMDD aproximations?
>> >> Thanks
>> >> Niurys
>> >>
>> >
>>
>
Dear all,
I personaly believe that using log-linear half-life calculated using the
biggest dose is the best (if not the "least worst") solution, even if it cannot
be pretended to be a beta-T1/2.
Indeed, deriving beta-T1/2 using linear PK parameters (V, CL,...) obtained from
a nonlinear PK model (Quasi-steady-state, Michaelis-Menten, etc) may lead to
surprising parameters.
Let us take as an example anti-PCSK9 mAbs, evolocumab and alirocumab. Using
the strategy consisting of the use of linear PK parameters, beta-1/2 were :
Evolocumab : beta-T/2 = 7.2 days (Gibbs, 2016) vs. 34 days (Kuchimanchi, 2018)
Alirocumab : beta-T1/2 = 29 days (Djebli, 2018) vs. 13 days (Martinez, 2018)
Therefore, an apparently nice nonlinear PK model does not imply a good
"separation" of linear and nonlinear parts, leading to possible
misspecification of linear elimination.
In addition, the interpretation of linear elimination is what is observed in
absence of antigen mass, and thus questions its relevance.
Best regards,
David
----- Mail original -----
Quoted reply history
De: "Saeheum Song" <[email protected]>
À: "Niurys.CS" <[email protected]>
Cc: "Peter Bonate" <[email protected]>, "Bill Denney"
<[email protected]>, "Justin Wilkins" <[email protected]>,
[email protected], "Leonid Gibiansky" <[email protected]>
Envoyé: Vendredi 30 Avril 2021 10:53:44
Objet: Re: [NMusers] Assessment of elimination half life of mAb
I would report maximum half life, where system is saturated with additional
statement of shorter when system is unsaturated.
This will satisfy clinicians queries, I believe
On Thu, Apr 29, 2021, 1:46 PM Niurys.CS < [email protected] > wrote:
Dear all,
I'm very grateful for these ideas and explanations. Actually, I was worry about
this topic. Previously, I reported the values of half life by NCA; however the
clinicians are asking for a half life value estimated by population PK.
Many thanks to you in the name of Cuban team.
Niurys
El 29/04/2021 12:49, "Bonate, Peter" < [email protected] > escribió:
All I can say is, Great minds.....
Maybe some of these ideas can help you, Niurys.
pete
Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS)
Clinical Pharmacology and Exploratory Development (CPED)
Astellas
1 Astellas Way, N3.158
Northbrook, IL 60062
[email protected]
(224) 619-4901
It’s been a while since I’ve had something here, but here is a Dad joke.
Question: Do you know why the math book was sad?
Answer: Because it had so many problems
-----Original Message-----
From: Leonid Gibiansky < [email protected] >
Sent: Thursday, April 29, 2021 11:42 AM
To: Justin Wilkins < [email protected] >; Bill Denney <
[email protected] >; Bonate, Peter < [email protected] >;
Niurys.CS < [email protected] >
Cc: [email protected]
Subject: Re: [NMusers] Assessment of elimination half life of mAb
still, half-life of the linear part could be helpful in cases when
non-linearity plays no significant role in elimination, so we tend to present
it together with the washout time simulations.
Leonid
On 4/29/2021 12:35 PM, Justin Wilkins wrote:
> Hi Bill, all,
>
> I do much the same thing - when there's nonlinearity happening, I've found it
> to be effective to plot concentration-time curves by doses and regimens of
> interest and mark the times at which the (median?) clinically-defined
> threshold for "washout" has been reached in each case. Of course this starts
> getting unwieldy when there are lots of doses or regimens. A less attractive
> way would be to produce a lookup table.
>
> Sounds like everyone's thinking along the same lines...
>
> Justin
>
>
> -----Original Message-----
> From: [email protected] < [email protected] > On
> Behalf Of Bill Denney
> Sent: Thursday, April 29, 2021 6:17 PM
> To: Bonate, Peter < [email protected] >; Leonid Gibiansky
> < [email protected] >; Niurys.CS < [email protected] >
> Cc: [email protected]
> Subject: RE: [NMusers] Assessment of elimination half life of mAb
>
> Hi Pete,
>
> I agree that it is hard to communicate. I like the general idea of C90 you
> propose. I tend to choose something in between your and Leonid's answer, when
> possible. I target an answer of "when is the pharmacodynamic effect <5% of
> the maximum or therapeutic effect". It does require more than just the PK,
> though. And for the just PK answer, I agree with Leonid and you, targeting
> some smallish fraction of Cmax is often reasonable for similar communication.
>
> What I find clinicians typically try to understand when the drug has washed
> out. The answer that many have reasonably latched onto is when 5 half-lives
> have passed, the drug is washed out. That suggests that about 3% (2^-5)
> effect is generally agreed as being washed out.
>
> To Niurys's question about a citation for this, I don't have one either.
> It's just a rule-of-thumb that I have tended to use.
>
> Thanks,
>
> Bill
>
> -----Original Message-----
> From: [email protected] < [email protected] > On
> Behalf Of Bonate, Peter
> Sent: Thursday, April 29, 2021 12:01 PM
> To: Leonid Gibiansky < [email protected] >; Niurys.CS
> < [email protected] >
> Cc: [email protected]
> Subject: RE: [NMusers] Assessment of elimination half life of mAb
>
> I've never really been happy with this. It's an unsatisfactory solution.
> You have a nonlinear drug. Let's assume you have an approved drug. It's given
> at some fixed dose. The clinician wants to know what is the drug's half-life
> so they can washout their patient and start them on some other therapy. We go
> back to them and say, we can't give you a half-life because it's a nonlinear
> drug, but once the kinetics become linear the half-life is X hours. That is a
> terrible answer. Maybe we need to come up with a new term, call it C90, the
> time it takes for Cmax to decline by 90%. That we can do. We don't even need
> an analytical solution, we can eyeball it. We could even get fancy and do it
> in a population model. C90 - the time it takes for Cmax to decline 90% in 90%
> of patients. Of course, for nonlinear drugs, C90 only holds for that dose.
> Change in dose results in a new C90.
> Just a thought.
>
> pete
>
>
>
> Peter Bonate, PhD
> Executive Director
> Pharmacokinetics, Modeling, and Simulation (PKMS) Clinical
> Pharmacology and Exploratory Development (CPED) Astellas
> 1 Astellas Way, N3.158
> Northbrook, IL 60062
> [email protected]
> (224) 619-4901
>
>
> It’s been a while since I’ve had something here, but here is a Dad joke.
>
> Question: Do you know why the math book was sad?
> Answer: Because it had so many problems
>
>
> -----Original Message-----
> From: [email protected] < [email protected] > On
> Behalf Of Leonid Gibiansky
> Sent: Thursday, April 29, 2021 9:54 AM
> To: Niurys.CS < [email protected] >
> Cc: [email protected]
> Subject: Re: [NMusers] Assessment of elimination half life of mAb
>
> I am not aware of any papers specifically addressing the half-live
> issue, but there are tons of original papers and tutorials on TMDD,
> just search the web Thanks Leonid
>
> On 4/29/2021 9:48 AM, Niurys.CS wrote:
>> Dear Leonid,
>>
>> Many thanks for clearing up my doubt. Can you suggest me any paper to
>> go into this topic in any depth.
>> Best,
>> Niurys
>>
>> El 28/04/2021 19:34, "Leonid Gibiansky" < [email protected]
>> <mailto: [email protected] >> escribió:
>>
>> There is no such thing as half-life of elimination for the nonlinear
>> drug. But one can compute something like half-life:
>>
>> 1. Half-life of the linear part (defined by CL, V1, V2, Q): this
>> defines the half-life at high doses/high concentrations when
>> nonlinear elimination is saturated.
>>
>> 2. Washout time: for the linear drug, 5 half-lives can be used to
>> define washout time. During this time, concentrations drop
>> approximately 2^5=32 times. So one can simulate the desired dosing
>> (single dose or steady state), find the time from Cmax to Cmax/32
>> and call it washout time (or time to Cmax/64 to be conservative)
>>
>> Thanks
>> Leonid
>>
>>
>> On 4/28/2021 5:17 PM, Niurys.CS wrote:
>>
>> Dear all
>> I need some help to assess the elimination half life of a
>> monoclonal antibody.
>> The model that describes the data is a QSS aproximation of TMDD
>> with Rmax constant. The model includes two binding process of
>> mAb to its target: in central and peripheral compartments.
>> Is there any specific equation to calcule lambda z and the
>> elimination half life for each of the TMDD aproximations?
>> Thanks
>> Niurys
>>
>