From: david.ternant

Date: Fri, 30 Apr 2021 13:16:04 +0200 (CEST)

Dear all,

I personaly believe that using log-linear half-life calculated using the bi=

ggest dose is the best (if not the "least worst") solution, even if it cann=

ot 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 l=

ead to surprising parameters.

Let us take as an example anti-PCSK9 mAbs, evolocumab and alirocumab. Usin=

g the strategy consisting of the use of linear PK parameters, beta-1/2 wer=

e :

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, 20=

18)

Therefore, an apparently nice nonlinear PK model does not imply a good "sep=

aration" of linear and nonlinear parts, leading to possible misspecificatio=

n of linear elimination.

In addition, the interpretation of linear elimination is what is observed i=

n absence of antigen mass, and thus questions its relevance.

Best regards,

David

----- Mail original -----

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 a=

bout this topic. Previously, I reported the values of half life by NCA; how=

ever the clinicians are asking for a half life value estimated by populatio=

n 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 i=

s 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-line=

arity plays no significant role in elimination, so we tend to present it to=

gether 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 regimen=

s of interest and mark the times at which the (median?) clinically-defined =

threshold for "washout" has been reached in each case. Of course this start=

s getting unwieldy when there are lots of doses or regimens. A less attract=

ive 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, targe=

ting some smallish fraction of Cmax is often reasonable for similar communi=

cation.

*>
*

*> 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-li=

ves 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 hal=

f-life so they can washout their patient and start them on some other thera=

py. 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 ho=

urs. That is a terrible answer. Maybe we need to come up with a new term, c=

all it C90, the time it takes for Cmax to decline by 90%. That we can do. W=

e 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 onl=

y 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 2^5=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
*

*>>
*

*>
*

Received on Fri Apr 30 2021 - 07:16:04 EDT

Date: Fri, 30 Apr 2021 13:16:04 +0200 (CEST)

Dear all,

I personaly believe that using log-linear half-life calculated using the bi=

ggest dose is the best (if not the "least worst") solution, even if it cann=

ot 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 l=

ead to surprising parameters.

Let us take as an example anti-PCSK9 mAbs, evolocumab and alirocumab. Usin=

g the strategy consisting of the use of linear PK parameters, beta-1/2 wer=

e :

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, 20=

18)

Therefore, an apparently nice nonlinear PK model does not imply a good "sep=

aration" of linear and nonlinear parts, leading to possible misspecificatio=

n of linear elimination.

In addition, the interpretation of linear elimination is what is observed i=

n absence of antigen mass, and thus questions its relevance.

Best regards,

David

----- Mail original -----

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 a=

bout this topic. Previously, I reported the values of half life by NCA; how=

ever the clinicians are asking for a half life value estimated by populatio=

n 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 i=

s 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-line=

arity plays no significant role in elimination, so we tend to present it to=

gether with the washout time simulations.

Leonid

On 4/29/2021 12:35 PM, Justin Wilkins wrote:

d it to be effective to plot concentration-time curves by doses and regimen=

s of interest and mark the times at which the (median?) clinically-defined =

threshold for "washout" has been reached in each case. Of course this start=

s getting unwieldy when there are lots of doses or regimens. A less attract=

ive way would be to produce a lookup table.

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, targe=

ting some smallish fraction of Cmax is often reasonable for similar communi=

cation.

ed out. The answer that many have reasonably latched onto is when 5 half-li=

ves have passed, the drug is washed out. That suggests that about 3% (2^-5)=

effect is generally agreed as being washed out.

iven at some fixed dose. The clinician wants to know what is the drug's hal=

f-life so they can washout their patient and start them on some other thera=

py. 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 ho=

urs. That is a terrible answer. Maybe we need to come up with a new term, c=

all it C90, the time it takes for Cmax to decline by 90%. That we can do. W=

e 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 onl=

y holds for that dose. Change in dose results in a new C90.

is a Dad joke.

Received on Fri Apr 30 2021 - 07:16:04 EDT