Hi again,
We have an inhaled drug model with parallel first-order absorption with two dose points and the fraction of absorbed dose defined as:
Dosepoint 1: Aa*F1
Dosepoint 2: Aa2*(1-F1)
however, whats become evident is there is a dose level depenancy.
What is the best way to model this in NLME:
(1) as a categorical covariate (have only 2 dose levels)
(2) as a continuous covariate
(3) include a new parameter Frel? and if so, how would this be incorporated in the graphical interface?
Thanks
Elliot
it will depend on the mechanism and where do you beleive there is a dose effect on FREL on Clearance ?
once you know what you are trying to test it will be easy to code it.
modeling it as a continuous might not be useful or possible since there is only two values.
Hi Simon,
We know the drug exhibits linear PK when given is other routes but we see non proportional PK between the two dose levels when we look at the NCA derived parameters. So we believe it the effect should be on the absorption piece.
If it’s categorical makes sense. But I’d like to know best way to do it given we have two dose points already with the relative fraction absorbed.
And would you check this covariate on all absorption parameters (Ka, tlag, etc…)
It is hard to provide further input without having a look at the data. What is the impact on AUC versus T1/2 versus Cmax and Tmax versus other paramteters that can be relevant ?
The absorption chain of events can mean different things: did you mean ka, gut transit, bioavailibiltiy etc. ?
let us assume you want to test dose as a covariate on Total F you might want to test two things:
Dose 1 relative total F versus Dose 2 and then at a later time test whehter the fraction absorbed by each mechanism change with the dose. ( not sure you will have enough data for this).
Regards,
Samer