RE: flip-flop without absorption information?
In comment to Shan’s statement:
It's my understanding that this flip-flop phenomenon is fundamentally a
mathematical problem -- that is, if we write down a PK model in its analytical
form, it becomes rather easy to understand that swapping the values between ka
and ke (CL/V) would lead to the same output.
This is not true. The values do not swap out. V will be different.
Consider a 1-compartment model with KA=0.1 per h, KEL=0.7 per h, and V1=125L.
Suppose a 250 mg dose is given. This model has flip-flop kinetics.
Now assume we build a model with KA=0.7 per h, KEL=0.1 per h, and V2 is
unknown, same dose. This model does not have flip-flop. Using the simulated
data from model 1 as the observed data for model 2, we can fit model 2 and find
the optimum value of V2. In this case it is 875L. If you look at the profiles
you will see that they are exactly the same.
So it’s not a matter of just changing the order of the exponents.
If you want to estimate the parameters of a flip-flop model you need a data
without absorption – IV. Or some other independent assessment of CL that does
not depend on absorption.
Peter Bonate, PhD
Executive Director
Pharmacokinetics, Modeling, and Simulation (PKMS)
Clinical Pharmacology and Exploratory Development (CPED)
Astellas
1 Astellas Way
Northbrook, IL 60062
[email protected]<mailto:[email protected]>
(224) 619-4901
Quote of the week –
“Dancing with the Stars” is not owned by Astellas.
Quoted reply history
From: [email protected] <[email protected]> On Behalf Of
Shan Pan
Sent: Tuesday, September 13, 2022 3:42 AM
To: Jakob Ribbing <[email protected]>; Niurys.CS
<[email protected]>
Cc: nmusers <[email protected]>
Subject: Re: [NMusers] flip-flop without absorption information?
This is an interesting discussion. At the same time I can't get my head around
the assumption of any covariate on a flip-flop phenomenon. In other words, even
if there is no information on covariates this phenomenon could still exist.
It's my understanding that this flip-flop phenomenon is fundamentally a
mathematical problem -- that is, if we write down a PK model in its analytical
form, it becomes rather easy to understand that swapping the values between ka
and ke (CL/V) would lead to the same output.
In the absence of data on drug absorption as in your case, I think the solution
could lie in fixing volume of distribution based on any prior information, e.g.
a reported value in the literature. Otherwise, try to fix it to a reasonable
estimate and see what happens.
Hope it helps.
Kind regards,
Shan
On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing
<[email protected]<mailto:[email protected]>> wrote:
Dear Niurys,
It would be down to distributional assumptions in that case.
For example if you have a very strong predictor (covariate) of either
elimination or absorption rate (but not both) - data could be informative to
discriminate between flip-flop or not.
Had your therapeutic been IgG monoclonal antibody, albumin wold have been a
predictor of the absolute CL that with a larger number of subjects may allow to
discriminate (especially if a mix of both healthy, and patients with higher
inflammation level and thereby lower albumin -> higher CL).
On the other hand, for example body weight would not be helpful in this regard.
Even if body weight would have an effect on CL and V, it would not have a major
impact on terminal elimination (and in addition one could have a concern on
body weight also affecting the absorption rate).
So you would need both the mechanistic knowledge on the covariate, for your
therapeutic peptide in the RA population, and it would need to be a strong
effect in sufficient number of subjects.
On such obvious covariate would be different routes of administration, where
nobody would question the mechanistic knowledge on that SC has a slower
absorption that IV :>)
In liu of IV dosing this becomes a more challenging task, however.
Best wishes
Jakob
On 13 Sep 2022, at 05:05, Niurys.CS
<[email protected]<mailto:[email protected]>> wrote:
Niurys
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