Hi Leonid, First of all thanks for your response saying half-life has no useful meaning for a drug with non-linear PK (clearance and/or volume, plasma protein binding, etc). Half-life is a useful parameter for some simple cases but when the question about the time course of drug effect then half-life has little value. Add in non-linear PK to the non-linear PD and then delayed concentration-effect makes it even harder. A simulation (a picture is worth a thousand words) can show the complexity and also give a 'feeling' for the answer to the question. Pseudo-solutions like the 'context sensitive half-life' should be avoided because half-life only has a scientifically useful meaning for first-order processes that can be visualised as exponential curves. Life is more than PK -- its PKPD is when it gets interesting (and complicated). Best wishes, Nick
-- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72 email: n.holf...@auckland.ac.nz http://holford.fmhs.auckland.ac.nz/ http://orcid.org/0000-0002-4031-2514 Read the question, answer the question, attempt all questions -----Original Message----- From: owner-nmus...@globomaxnm.com <owner-nmus...@globomaxnm.com> On Behalf Of Leonid Gibiansky Sent: Thursday, 29 April 2021 6:42 PM 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 >> >
