Bioequivalence and Bioavailability Forum • OT: Bias of AUCt, AUCall, pAUC

OT: Bias of AUCt, AUCall, pAUC [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2020-06-08 17:53 (1558 d 02:03 ago) – Posting: # 21512
Views: 12,999

Hi ElMaestro,

❝ […] it will not necessarily imply a bias on the BE conclusion unless someone can prove that E(ln(AUC_all,T - ln(AUC_all,R)) does not equal E(ln(AUC_T) - ln(AUC_R)), regardless of whether the latter is expressed as AUCinf or AUCt.

There will always be a bias in any AUC-approach if BQLs come into play and the true T/R-ratio is not ~~exactly~~ sufficiently close to unity. Exceptions: Comparison of (reliably) estimated AUC_0–∞ or AUC_{0–t(common)}.

Since the bias will point away from unity, the T/R-ratio will get worse and regulators don’t care (wrong but conservative).

Example: I used the C1-column of this post as the reference (complete data). Then I generate three others (T) as R/2. Lin-up/log-down trapezoidal AUCs. The T/R-ratio should be 0.5.

Complete data
PK metric T R T/R %RE AUClast 1217.3 2434.6 0.500 ±0.00 AUCall 1217.3 2434.6 0.500 ±0.00 AUCcommon 1093.8 2187.5 0.500 ±0.00 AUC72 1217.3 2434.6 0.500 ±0.00 AUCinf 1298.4 2596.9 0.500 ±0.00
C₇₂ of T missing
PK metric T R T/R %RE AUClast 1093.8 2434.6 0.449 –10.20 AUCall 1093.8 2434.6 0.449 –10.20 AUCcommon 1093.8 2187.5 0.500 ±0.00 AUC72 1216.6 2434.6 0.500 ±0.00 AUCinf 1297.2 2596.9 0.500 ±0.00
C₇₂ of T set to zero
PK metric T R T/R %RE AUClast 1093.8 2434.6 0.449 –10.20 AUCall 1188.0 2434.6 0.488 –2.40 AUCcommon 1093.8 2187.5 0.500 ±0.00 AUC72 1188.0 2434.6 0.488 –2.40 AUCinf 1297.2 2596.9 0.500 ±0.00

As I wrote above, if we have missing(s) only AUC_0–∞ and AUC_{0–t(common)} are unbiased regardless the chosen method.

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Helmut Schütz

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Science Quotes

Complete thread:

AUCt not covering at least 80% of AUCinf ratnakar1811 2013-03-05 08:30 [Regulatives / Guidelines]
- AUCt not covering at least 80% of AUCinf d_labes 2013-03-05 11:12
  - AUCt not covering at least 80% of AUCinf ratnakar1811 2013-03-06 08:50
    - AUCt not covering at least 80% of AUCinf ElMaestro 2013-03-06 11:10
      - ADME-tox? Helmut 2013-03-06 14:35
        
        ADME-tox? ElMaestro 2013-03-06 16:40
        
        OT Helmut 2013-03-06 17:19
        
        OT ElMaestro 2013-03-07 17:19
        
        OT Helmut 2013-03-07 17:26
    - Science vs. regulations Helmut 2013-03-06 14:30
      - Science vs. regulations cakhatri 2013-03-10 08:59
        
        ratio = difference of logs! Helmut 2013-03-11 01:17
      - Science vs. (EMA) GL aka PK primer Helmut 2013-03-11 03:17
      - Science vs. regulations qualityassurance 2020-04-23 14:11
        
        Science vs. regulations Helmut 2020-04-23 17:32
        
        Science vs. regulations Achievwin 2020-05-07 22:59
        
        Science vs. regulations Helmut 2020-05-07 23:54
    - AUCt not covering at least 80% of AUCinf Brus 2018-11-20 13:01
      - AUCt not covering at least 80% of AUCinf Astea 2020-06-05 19:05
        
        So what? Helmut 2020-06-06 12:02
        
        Carrot and whip Astea 2020-06-06 21:11
        
        Gedankenexperiment Helmut 2020-06-07 12:41
        
        Dead dogs mittyri 2020-06-07 20:32
        
        Aber meine Herren das ist keine physik Astea 2020-06-08 00:08
        
        Aber meine Dame, das ist alles Unsinn! Helmut 2020-06-08 01:04
        Bizarre paper Helmut 2020-06-08 12:43
        
        Bizarre paper ElMaestro 2020-06-08 15:33
        
        OT: Bias of AUCt, AUCall, pAUCHelmut 2020-06-08 15:53
        
        OT: Bias of AUCt, AUCall, pAUC ElMaestro 2020-06-09 08:45
        
        OT: Bias of AUCs; example Helmut 2020-06-09 14:07
        
        Maxwell's demon Astea 2020-06-12 14:15
        
        Dead dogs Helmut 2020-06-08 10:40