Re: Assessment of elimination half life of mAb

On Thu, Apr 29, 2021 at 1:11 PM David at Booomer <[email protected]> wrote: > 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 helps > 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 <[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 > > >> > > > > > >