Hi Niurys, Depending on the size of your peptide and the timing of the first observations, it might also be likely that the rate limiting step for the terminal elimination phase is the (re)distribution from the peripheral to the central compartment, rather than the absorption. This is nicely demonstrated for small proteins in figure 3 of this paper by Li and Shah, where you see the impact of size mainly on the initial phase of the PK curves, rather than the elimination phase, and this is nicely captured by the PBPK model. https://pubmed.ncbi.nlm.nih.gov/31028591/ Coming back to your question if this can be evaluated without data in the first phase, you would need other information on the clearance. This could be derived from covariate relationships as Jakob suggested, or from prior knowledge on the expected Clearance. You could use, for example, the assumption that the clearance is equal to the GFR and see how that relates to your data, possibly extended with absorption/distribution parameters based on the two-pore model (and the molecular weight). Best,
Wilbert de Witte Op di 13 sep. 2022 om 10:53 schreef Shan Pan <shanpan1...@gmail.com>: > 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 < > jakob.ribb...@pharmetheus.com> 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 <amaranth...@gmail.com> 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 here <https://pharmetheus.com/privacy-policy/>.* >> >
