MD design based on SD data [Design Issues]

posted by Helmut Homepage – Vienna, Austria, 2016-03-15 17:39 (3260 d 02:07 ago) – Posting: # 16106
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Hi BE-proff,

❝ If I need to compare kinetics of immediate-release tablet and modified-release medication how to plan a study?


I guess you are talking BE and not PK (modeling)?

❝ Which parameters are to be used?


Nitpicking: PK parameters are estimated by a PK model. PK metrics are obtained by NCA/SHAM. ;-)

❝ How to determine how many days and how often tablets are to be taken?


If linear PK is applicable, 5–7 times t1/2 (AFAIK, only ANVISA requires 10×t1/2 ~99.9% of steady state). Exact for the one-compartment model and approximate for >1 compartments. In theory steady state (output = input) is reached after infinite time. We don’t want to wait that long, right? Formula to estimate the percentage of steady state reached: 100(1–½i), where i is the i-th dose administered.
As said above all this is valid for linear PK only (check the literature). For nonlinear PK it might get extremely complicated (see this thread) and designing an MD study without knowing the kind of nonlinearity and establishing a PK model first might be almost impossible.

❝ How to determine what time point must be in PK-session?


You need to have single dose data (preferably of your own study). Some people design the MD dose study already based on literature data of the IR formulation and black magic assumptions about the new MR formulation. Not a good idea!
Based on SD data you could use a method called Nonparametric Superposition (see this thread for software and this post for an example). Essentially at every dosing you stack the single dose profile on top of the expected concentrations of previous doses estimated by λz. If the software allows that you may explore different sampling schedules (i.e., interpolating time points not existing in the SD profiles). Remember that a precise estimate of Css,max is crucial. Since tss,max for IR and MR will be different, try to find a sampling schedule which will give you sufficient information about both.

❝ A lot of questions... :confused:


Some answers, I do hope.

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