Bioequivalence and Bioavailability Forum

Hi Biostats,

❝ As per the EMEA definition …

The EMEA lost its second E in 2005.

❝ … of Ctau,ss, Ctau,ss is the Concentration at the end of the dosing interval at steady state.

Correct.

❝ I want to know the significance of Ctau,ss values in steady study?

Required acc. to the GL.
If you compare formulations with different release rates (say CR vs. IR) that’s a hybrid application in the EEA and therapeutic studies might be waived under certain circumstances (see the GL Section 5.2.1).

❝ What is the interpretation of Ctau,ss?

Good question. In the current regulatory thinking BE is a comparison of the biopharmaceutical performance of formulations (release tested in human “test-tubes”). Similar PK profiles in healthy subjects are assumed to give similar therapeutic responses in patients.
However, this approach mixes up PK with PD, i.e., assumes that C_max,ss is a measure of safety and the extent of absorption a measure of the effect. Here C_τ,ss enters the scene. Whereas C_max,ss is believed to be related to toxicity, C_τ,ss is believed to be related to some kind of “minimum required effect”. Hence, an alternative approach to testing equivalence of C_max,ss and C_τ,ss is the so-called “bracketing approach”, where you perform one-sided tests (non-superiority of C_max,ss and non-inferiority of C_τ,ss). For an example see there.