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 >
