Bioequivalence and Bioavailability Forum

Dear Nirali!

❝ Is calculation of 90%CI required for AUCINF while doing ANVISA submission

❝ for 72hrs truncated single dose, crossover BE study?

IMHO, it's neither necessary (ANVISA 896/03, Annex, Section n)

'in the case of drugs presenting long elimination half life (over 24 hours), an alternative collection schedule may be used, of up to 72 hours, allowing the determination of the area under the fragmented curve (ASC0-72), or a parallel study.'

and (ANVISA 1170/06, Anexo, Section q)

'no caso de fármacos que apresentam meia-vida de eliminação longa (superior a 24 horas), poderá ser utilizado um cronograma de coletas alternativo, no mínimo de 72 horas, que possibilite a determinação da área sob a curva truncada (ASC0-72), ou um estudo paralelo;'

...

❝ Product has long half life-70hrs. Therefore planned to truncate AUC upto

❝ 72hrs. ANVISA guideline has not clearly mentioned that 90%CI for AUCINF is

❝ required or not, for the same.

... nor possible at all in your case.
How would you extrapolate? With such a half-life you never will be able to get a least 3 sampling points in the terminal phase!

❝ Would you pls explain the importance of AUCINF in 72hrs-truncated BE

❝ study?

Zero. The idea behind truncated AUC is not extrapolating. It has been demonstrated that for t > 2-3×t_max the outcome (PE, CI) does not essentially change, with the exception that variability increases (i.e., the CI becomes wider). The higher variability is caused by the uncertainty in extrapolation (concentrations appoaching the limit of quantitation). This is also the rationale behind many Guidances (Europe, ASEAN States, Australia, New Zealand, South Africa,...) where AUC_last (not AUC_inf!) is the primary metric for total exposure.
72h have their origin in the maximum observed residence time in the GI tract.