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Re: Assessment of elimination half life of mAb

From: Ayyappa Chaturvedula <ayyappach>
Date: Thu, 29 Apr 2021 15:37:35 -0500

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


On Thu, Apr 29, 2021 at 1:11 PM David at Booomer <david

> 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 h=
elps
> 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 <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
> 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
> > Peter.bonate
> > (224) 619-4901
> >
> >
> > It’s been a while since I’ve had something here, but he=
re 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
> wdenney
> Niurys.CS <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
> 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: 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 you propose. I tend to choose something in between your and Leonid's
> answer, when possible. I target an answer of "when is the pharmacodynami=
c
> 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 Leoni=
d
> 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: 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 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. C9=
0
> - the time it takes for Cmax to decline 90% in 90% of patients. Of cours=
e,
> 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 t=
o
> > >> 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): thi=
s
> > >> 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 Thu Apr 29 2021 - 16:37:35 EDT

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