Re: 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
Quoted reply history
On Tue, Sep 13, 2022 at 5:36 AM Jakob Ribbing <[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]> wrote:
>
> Niurys
>
>
>
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