Posting: # 20636
I would like to ask help for understand the objetive of the steady state study when you are comparing a MR formulation with a IR formulation. The objective would be compare the effect of the accumulation? Is there any reason to conduct the study only with de highest dose?
Edit: Please follow the Forum’s Policy. [Helmut]
Posting: # 20639
» I would like to ask help for understand the objetive of the steady state study when you are comparing a MR formulation with a IR formulation.
I don’t know the current state of affairs in Brazil. I don’t speak Portuguese and the English site is practically useless. Sorry.
» The objective would be compare the effect of the accumulation?
That a drug accumulates is trivial. The question is only, how much and whether the drug follows linear PK. That’s already established by the originator. A study in a paired design; SD → saturation → (pseudo-) steady state.
» Is there any reason to conduct the study only with de highest dose?
EMA again: In general the highest dose because – if linear PK is established – the other strengths can be waived. Makes sense. “Perfect” dose-proportionality (slope β of the power model = 1) is rare. Metabolic saturation is more common than induction. Furthermore, the GL asks for the “most sensitive strength”. Might be difficult to know beforehand. If case of nonlinear PK it might be the lowest strength as well.
Another trap (EMA GL Section 5.1.1):
Fluctuation in drug concentrations should be studied following repeated dosing. Unless otherwise justified, the modified release product should produce similar or less fluctuations as the immediate release product.(my emphasis)
That’s a one-sided test (‘non-superiority’) and not the two-sided test for equivalence. For the same variability and T/R-ratio <1 you need a lower sample size. Example:
Only if the T/R-ratio is >1 it will get nasty. Try
Some people decided to ignore the comparison of %PTF and opt for the so-called “bracketing approach” instead, where Cmin is assessed for ‘non-inferiority’ (surrogate for efficacy) and Cmax for ‘non-superiority’ (surrogate for safety).
The quality of responses received is directly proportional to the quality of the question asked. ☼