Bioequivalence and Bioavailability Forum

Hi M.tareq,

❝ "A statistical evaluation of tmax is not required …

Unfortunately the EMA is so allergic to a nonparametric test that it was removed from the GL.

❝ … if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, …

We had to accept that BE is seen a “quality measure”. Why the heck does clinical relevance come back here?

❝ … there should be no apparent difference in median tmax and its variability between test and reference product."

Oh dear! Apparent? Variability of the median? WTF? The median is an estimate. The data is variable.

❝ If a fast disintegrating tab has a tmax earlier than the conventional release, does it prove that it has an earlier onset of action?

Not the slightest idea. First of all, t_max is a very poor predictor of differences in the rate of absorption.
Example: One compartment model; F_T=F_R=1, k_el 0.1733 h^–1 (t_½ 4 h), k_abs,R 1.3863 h^–1 (t_½ 30 min), k_abs,T 2.0794 h^–1 (t_½ 20 min), sigmoidal effect model identical for T and R; E_max 125, EC₅₀ 50, γ 0.25.

  t       C (R)   C (T)        E (R)   E (T)
 0.0000    0.00    0.00         0.00    0.00
 0.0833    9.48   14.48        49.69   52.89
 0.1667   17.78   26.44        54.47   57.53
 0.2500   25.05   36.30        57.11   60.00
 0.3333   31.39   44.39        58.87   61.57
 0.5000   41.70   56.35        61.08   63.43
 0.7500   52.46   66.79        62.87   64.76
 1.0000   59.09   71.59        63.80   65.30
 1.2500   62.85   73.09        64.29   65.46
 1.5000   64.61   72.69        64.50   65.42
 2.0000   64.46   69.15        64.48   65.03
 2.7500   59.88   61.76        63.91   64.15
 4.0000   49.61   49.98        62.44   62.50
 6.0000   35.33   35.35        59.79   59.79
 8.0000   25.00   25.00        57.10   57.10
12.0000   12.50   12.50        51.78   51.78
16.0000    6.25    6.25        46.61   46.61
24.0000    1.56    1.56        37.00   37.00
tmax       1.50    1.25  tmax   1.50    1.25
 Δ                –0.25   Δ            –0.25
Cmax      64.61   73.09  Emax  64.50   65.46
 T/R             113.13%  T/R          101.49%
λz       0.1733  0.1733  λz   0.0281   0.0281
AUCt     494.87  519.25  AUECt 1236.8  1240.5
AUC∞     503.89  528.26  AUEC∞ 2552.3  2556.0
 T/R             104.84%  T/R          100.15%

Although the test has a 50% (!) faster absorption than the reference, t_max of T is only 15 min earlier than the one of R (reflected both in PK and PD). The T/R-ratio of C_max is 113% but the maximum effect increases by only 1.5%! Is that relevant?
This is a very simple PK/PD-link model. With others (e.g., incorporating a delay in onset) the observed difference in PK may disappear completely in PD. If we have no data about the PK/PD-relationship we are left out in the dark. I’m aware of only a few studies (rapid onset for multiphasic release products of zolpidem and methylphenidate).