Bioequivalence and Bioavailability Forum

Urban legend? [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2008-11-21 17:06 (6053 d 10:05 ago) – Posting: # 2769
Views: 23,449

Dear all!

❝ Exactly. From a PK point of view it's possible to show that C_max is less sensitive to differences then AUC if going from single dose to steady state (this statement is also given in the earlier sentence).

❝ [...] it's possible to show it by simulations. I have the references somewhere, [...]

❝ But you can do it on your own: Fire up some PK software (even M$-Excel would do the job) - define parameters of two hypothetical formulations in such a way that C_max is let's say 10% apart - go into steady state - the difference should be smaller.

Really?
Or just an Urban legend of the pharmacokinetolophystic (© ElMaestro) type?

single dose
AUC_inf
T 84.02 ng*h/ml
R 93.35 ng*h/ml
T/R 90 %
C_max
T 5.84 ng/ml
R 6.49 ng/ml
T/R 90 %
steady state
AUC_tau
T 83.31 ng*h/ml
R 92.56 ng*h/ml
T/R 90 %
C_max
T 10.84 ng/ml
R 11.64 ng/ml
T/R 90 %

T/R_{steady state} = T/R_{single dose} = 90%, both for AUC and C_max. Of course C_max values in steady state are further apart (0.80 ng/ml) than after a single dose (0.65 ng/ml), but the ratio stays the same. Am I missing something?
If somebody is interested in repeating the simulation: I used WinNonlin's Exp1.pwo dataset (like in this post), and changed F from 1 (Reference) to 0.9 (Test).
  h    ng/ml
 0.1   2.6
 0.25  4.817
 0.5   6.596
 0.75  6.471
 1     6.049
 1.5   5.314
 2     4.611
 2.5   4.5
 3     4.392
 4     4.013
 5     3.698
 6     3.505
 8     3.382
12     2.844
14     2.383
24     1.287

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Helmut Schütz


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Complete thread:

• Critical review of EU BE guideline (Rev.1) Helmut 2008-08-22 14:30 [Regulatives / Guidelines] 
  • Critical review of EU BE guideline (Rev.1) d_labes 2008-08-22 15:42
    • Critical review of EU BE guideline (Rev.1) Helmut 2008-08-23 02:02
      • Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 09:14
        • Variations Helmut 2008-08-25 11:06
  • Critical review of EU BE guideline (Rev.1) Jaime_R 2008-08-23 16:47
    • Critical review of EU BE guideline (Rev.1) Ravi 2008-08-25 08:19
      • Two Stage Design Helmut 2008-08-25 11:43
        • Two Stage Design JPL 2008-08-28 09:44
          • Two Stage Design Helmut 2008-08-28 11:50
            • Two Stage Design d_labes 2008-08-28 12:09
            • Sequential Design Helmut 2008-11-05 13:22
    • Critical review of EU BE guideline (Rev.1) banusunman 2008-08-26 16:56
      • Washout Helmut 2008-10-15 16:02
  • Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 09:49
    • Critical review of EU BE guideline (Rev.1) Helmut 2008-08-25 12:11
      • Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 13:03
      • Urban legend?Helmut 2008-11-21 16:06
        • Urban legend? d_labes 2008-11-24 15:06
  • Critical review of EU BE guideline (Rev.1) d_labes 2008-08-25 11:16
  • Critical review of EU BE guideline (Rev.1), tmax, MRT, LZ d_labes 2008-08-25 11:32
    • Critical review of EU BE guideline (Rev.1), tmax, MRT, LZ Helmut 2008-08-25 13:10
    • tmax, nonparametrics Helmut 2008-10-13 15:38
      • tmax, nonparametrics d_labes 2008-10-14 08:33
        • tmax, nonparametrics Helmut 2008-10-14 11:29
        • tmax, Canadian approach Helmut 2008-11-21 15:41
          • tmax, Canadian approach d_labes 2008-11-24 13:53
            • Early exposure, Canadian approach: GMR only! Helmut 2009-02-08 00:44
              • Early exposure, Canadian approach: GMR only! d_labes 2009-02-09 08:50
          • tmax; another example Helmut 2008-12-25 15:59
  • Automatic integration janmacek 2008-08-27 12:21
    • Automatic integration Ohlbe 2008-08-27 14:49
      • Manual reintegration! H_Rotter 2008-08-28 11:28
        • Manual reintegration! ElMaestro 2008-08-28 12:44
  • Subject accountability, Proc MIXED or equivalent d_labes 2008-09-02 11:13
    • Subject accountability, Proc MIXED or equivalent Ohlbe 2008-09-02 15:20
      • Subject accountability, Proc MIXED or equivalent d_labes 2008-09-02 16:30
  • partial AUC, early exposure d_labes 2008-09-03 08:35
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    • HVDs? d_labes 2008-09-23 14:20
    • HVDs? Helmut 2009-01-20 14:33
    • E.g., omeprazole Helmut 2009-03-06 17:21
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    • Dissolution update Helmut 2008-10-13 12:43
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