RE: flip-flop without absorption information?
Hi Jakob and Everyone,
In the no-covariate case flip and flop 😊 represent equal likelihoods i.e. two
local minimums of equal depth.
I agree that distributional assumptions would likely be useful to discriminate
between two different parameters values that have equal likelihoods.
Depending on how much information is contained in the covariate then minimum
might “shift” so that one becomes the global minimum and the other a local
minimum.
But one should be aware that local minimums could be present and influence
NONMEM estimation.
Warm regards,
Douglas
Quoted reply history
Van: [email protected] <[email protected]> Namens Jakob
Ribbing
Verzonden: dinsdag 13 september 2022 06:23
Aan: Niurys.CS <[email protected]>; nmusers <[email protected]>
Onderwerp: Re: [NMusers] flip-flop without absorption information?
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
This communication is confidential and is only intended for the use of the
individual or entity to which it is directed. It may contain information that
is privileged and exempt from disclosure under applicable law. If you are not
the intended recipient please notify us immediately. Please do not copy it or
disclose its contents to any other person.
Any personal data will be processed in accordance with Pharmetheus' privacy
notice, available
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fpharmetheus.com%2Fprivacy-policy%2F&data=05%7C01%7Cd.j.eleveld%40umcg.nl%7Cd9d9d66771e044080b8908da9540f3ac%7C335122f9d4f44d67a2fccd6dc20dde70%7C0%7C0%7C637986403439146794%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=Va6LIYK0s9Pkvv4AL9e%2FQ0dxdVwOgUBaSFhsU81dTAY%3D&reserved=0.
________________________________