Log in
RegisterAnswer machine [RSABE / ABEL]
Dear Helmut!
My answer is somefink like (may be it helps others):
The concentration time points selected for calculation of the terminal rate constant (lambdaZ) are chosen by visual inspection as recommended in the literature.
The last concentration of the questioned terminal rate constant calculations does not fit the linear part of the concentration time curves (in log-linear plot). This behaviour is sometimes common if the concentrations are in the range of the LLOQ. To not grossly overestimate the terminal half-life in such cases it is recommended to leave out such measurement points. See for instance the book
Hauschke, Steinijans, Pigeot
"Bioequivalence Studies in Drug Development"
Wiley, Chichester (2007)
Chapter 2 “Metrics to characterize concentration-time profiles in single- and multiple-dose bioequivalence studies” especially Fig. 2.3
AUC(0-inf) in itself is not a primary endpoint on which the bioequivalence decision will be based (not according to the EMA guidance and also not according to the Study protocol). The bioequivalence decision taken in the Study Report is thus in no way affected by the way of calculation of the terminal rate constant.
❝ Oh no! What will you answer? Maybe this post helps. Seems that (some) regulators are not aware about the consequences of (acceptable!) limitations of analytical methods (20% inaccuracy, 20% imprecision at the LLOQ) and take results as set in stone. ...
My answer is somefink like (may be it helps others):
The concentration time points selected for calculation of the terminal rate constant (lambdaZ) are chosen by visual inspection as recommended in the literature.
The last concentration of the questioned terminal rate constant calculations does not fit the linear part of the concentration time curves (in log-linear plot). This behaviour is sometimes common if the concentrations are in the range of the LLOQ. To not grossly overestimate the terminal half-life in such cases it is recommended to leave out such measurement points. See for instance the book
Hauschke, Steinijans, Pigeot
"Bioequivalence Studies in Drug Development"
Wiley, Chichester (2007)
Chapter 2 “Metrics to characterize concentration-time profiles in single- and multiple-dose bioequivalence studies” especially Fig. 2.3
AUC(0-inf) in itself is not a primary endpoint on which the bioequivalence decision will be based (not according to the EMA guidance and also not according to the Study protocol). The bioequivalence decision taken in the Study Report is thus in no way affected by the way of calculation of the terminal rate constant.
—
Regards,
Detlew
Regards,
Detlew
Complete thread:
- SAS error in 3 way ref replicate study AB 2012-05-04 15:13 [RSABE / ABEL]
![[Mix]](https://static.bebac.at/img/mix.png "open in Mix view")
- SAS error in 3 way ref replicate study jag009 2012-05-04 15:36
- SAS error in 3 way ref replicate study AB 2012-05-05 06:45
- FDA's ABE code and partial replicate design d_labes 2012-05-06 10:10
- Arbitrary (and unjustified) cut-off of r² Helmut 2012-05-06 13:29
- Anscombe quartet d_labes 2012-05-07 08:48
- Anscombe quartet in R Helmut 2012-05-07 11:15
- Anscombe quartet in R AB 2012-05-07 12:07
- Anscombe quartet in R Helmut 2012-05-07 11:15
- Arbitrary (and unjustified) cut-off of r² FI 2012-10-08 10:39
- Predominant half life; exclusions Helmut 2012-10-08 13:45
- Excluding time points for lambdaZ d_labes 2012-10-09 09:33
- Analytical variability Helmut 2012-10-09 14:09
- Answer machined_labes 2012-10-09 15:15
- Well done! Helmut 2012-10-09 19:43
- Answer machined_labes 2012-10-09 15:15
- Analytical variability Helmut 2012-10-09 14:09
- Excluding time points for lambdaZ d_labes 2012-10-09 09:33
- Predominant half life; exclusions Helmut 2012-10-08 13:45
- Anscombe quartet d_labes 2012-05-07 08:48
- Arbitrary (and unjustified) cut-off of r² Helmut 2012-05-06 13:29
- SAS error in 3 way ref replicate study jag009 2012-05-04 15:36
Ing. Helmut Schütz