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Back to the forum  Query: 2017-10-21 00:56 UTC (UTC+2h)
 
M.tareq
Junior

2017-10-12 05:53

Posting: # 17890
Views: 339
 

 Clinical significance of Tmax [Regulatives / Guidelines]

Dear all ,

I have a question about Tmax from clinical perspective.

According to EMA guidance:
"A statistical evaluation of tmax is not required. However, if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, there should be no apparent difference in median tmax and its variability between test and reference product."

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

Thanks in advance and Best regards
Helmut
Hero
Homepage
Vienna, Austria,
2017-10-12 11:22

@ M.tareq
Posting: # 17891
Views: 274
 

 Clinical significance of Tmax

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?

» 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, tmax is a very poor predictor of differences in the rate of absorption.
Example: One compartment model; FT=FR=1, kel 0.1733 h–1 (t½ 4 h), kabs,R 1.3863 h–1 (t½ 30 min), kabs,T 2.0794 h–1 (t½ 20 min), sigmoidal effect model identical for T and R; Emax 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     504.99  529.50  AUECt 1236.8  1240.5
AUC∞     514.01  538.52  AUEC∞ 2552.3  2556.0
 T/R             104.77%  T/R          100.15%


[image]


Although T has a 50% (!) faster absorption than R, tmax of T is only 15 min earlier than the one of R (reflected both in concentrations and effects). The T/R-ratio of Cmax is 113% but the maximum effect increases by only 1.5%! Is that relevant?
This 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 products of zolpidem and methlyphenidate).

[image]All the best,
Helmut Schütz 
[image]

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