Re: Assessment of elimination half life of mAb

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 >> >> >> > >> >