Dear all, I personaly believe that using log-linear half-life calculated using the biggest dose is the best (if not the "least worst") solution, even if it cannot 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 lead to surprising parameters.
Let us take as an example anti-PCSK9 mAbs, evolocumab and alirocumab. Using the strategy consisting of the use of linear PK parameters, beta-1/2 were : 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, 2018) Therefore, an apparently nice nonlinear PK model does not imply a good "separation" of linear and nonlinear parts, leading to possible misspecification of linear elimination. In addition, the interpretation of linear elimination is what is observed in absence of antigen mass, and thus questions its relevance. Best regards, David ----- Mail original ----- De: "Saeheum Song" <ss.pkpdmo...@gmail.com> À: "Niurys.CS" <amaranth...@gmail.com> Cc: "Peter Bonate" <peter.bon...@astellas.com>, "Bill Denney" <wden...@humanpredictions.com>, "Justin Wilkins" <justin.wilk...@occams.com>, nmusers@globomaxnm.com, "Leonid Gibiansky" <lgibian...@quantpharm.com> 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 < amaranth...@gmail.com > 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" < peter.bon...@astellas.com > 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.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: Leonid Gibiansky < lgibian...@quantpharm.com > Sent: Thursday, April 29, 2021 11:42 AM To: Justin Wilkins < justin.wilk...@occams.com >; Bill Denney < wden...@humanpredictions.com >; Bonate, Peter < peter.bon...@astellas.com >; Niurys.CS < amaranth...@gmail.com > Cc: nmusers@globomaxnm.com 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-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 >> >
