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-nmus...@globomaxnm.com <owner-nmus...@globomaxnm.com> On Behalf Of
Bill Denney
Sent: Thursday, April 29, 2021 6:17 PM
To: Bonate, Peter <peter.bon...@astellas.com>; Leonid Gibiansky
<lgibian...@quantpharm.com>; Niurys.CS <amaranth...@gmail.com>
Cc: nmusers@globomaxnm.com
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: owner-nmus...@globomaxnm.com <owner-nmus...@globomaxnm.com> On Behalf Of
Bonate, Peter
Sent: Thursday, April 29, 2021 12:01 PM
To: Leonid Gibiansky <lgibian...@quantpharm.com>; Niurys.CS
<amaranth...@gmail.com>
Cc: nmusers@globomaxnm.com
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
peter.bon...@astellas.com
(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-nmus...@globomaxnm.com <owner-nmus...@globomaxnm.com> On Behalf Of
Leonid Gibiansky
Sent: Thursday, April 29, 2021 9:54 AM
To: Niurys.CS <amaranth...@gmail.com>
Cc: nmusers@globomaxnm.com
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" <lgibian...@quantpharm.com
<mailto:lgibian...@quantpharm.com>> 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
