Kelen ☆ Brazil, 20190920 20:04 (488 d 17:12 ago) Posting: # 20636 Views: 3,586 

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] 
Helmut ★★★ Vienna, Austria, 20190923 10:04 (486 d 03:11 ago) @ Kelen Posting: # 20639 Views: 2,867 

Hi Kelen, » 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” doseproportionality (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 onesided test (‘nonsuperiority’) and not the twosided test for equivalence. For the same variability and T/Rratio <1 you need a lower sample size. Example:
Only if the T/Rratio is >1 it will get nasty. Try
Some people decided to ignore the comparison of %PTF and opt for the socalled “bracketing approach” instead, where C_{min} is assessed for ‘noninferiority’ (surrogate for efficacy) and C_{max} for ‘nonsuperiority’ (surrogate for safety). — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
apapanas ☆ Greece, 20200624 14:25 (210 d 22:51 ago) @ Helmut Posting: # 21574 Views: 1,581 

Dear Helmut, Is there a threshold value for linearity indexes (AUC0tau,ss / AUC0inf, SD) over which the superposition principle is no longer applicable? Thank you in advance. Kindest regards, Antigoni 
Helmut ★★★ Vienna, Austria, 20200624 14:38 (210 d 22:37 ago) @ apapanas Posting: # 21575 Views: 1,565 

Γειά σου Αντιγόνη! » Is there a threshold value for linearity indexes (AUC0tau,ss / AUC0inf, SD) over which the superposition principle is no longer applicable? Very good question! At least originators regularly use the common 80.00–125.00%. — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
apapanas ☆ Greece, 20200624 15:32 (210 d 21:43 ago) @ Helmut Posting: # 21576 Views: 1,546 

» Γειά σου Αντιγόνη! » » » Is there a threshold value for linearity indexes (AUC0tau,ss / AUC0inf, SD) over which the superposition principle is no longer applicable? » » Very good question! At least originators regularly use the common 80.00–125.00%. Ευχαριστω πολυ! 