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I do not have so much experience with PK so hopefully you can help me with some questions?
I am trying to calculate AUCinf with WinNonLin using NCA (Lin down and Log up Method). I am
analyzing a drug with an enterohepatic recirculation and an enteric coated formulation. Sometimes
it seems to me that patients took their drug not after the last blood sample was collected (t=12h)
but much earlier (I have an increase in the concentration after the EHC beginning with t=10h).
WinNonLin does not compute AUCinf when the concentration increases over time at the end of the
dosing interval or it calculates an AUCinf which is really high. The difference between AUCo-12h and
AUCinf are sometimes at about 50%. I am not quite sure if this is ok?
I tried to set up the time points for calculating lambda manually but I am not sure if it is ok to
set up the times point (t=5h) before the enterohepatic recirculation starts (for example t=8h). Or
is it better to exclude this PK profiles?
It would be really nice if you can help me!
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if you collect the final sample at 12h and EHC starts at 10h the probability is quite high that you
miss the terminal elimination phase of the profiles. However, for the correct calculation of AUCinf
it is mandatory that you can estimate the terminal slope. Since you don't have decreasing
concentrations the slope will either be close to zero or even be positive. Consequently, the
extrapolated portion of the AUCinf is unacceptably high (>20%) or cannot be calculated at all.
Manually setting up the points for the regression line will not solve this problem.
Maybe the following points will help to improve the situation:
1) use AUClast instead of AUCinf to assess exposure in your trial. It might also be helpful to
define a partial AUC area e.g. from 0 to 10h (when EHC begins).
2) increase the blood sample collection time in upcoming trials to cover the terminal elimination
phase of the compound. If the terminal half life is known you should place the final sample at tmax
+ 3.5 half-lifes. Depending on the characteristics of the EHC it might be justified to extend the
collection interval even more.
3) if you want to learn about the impact of EHC you should set up an adequate model in WinNonLin to
analyze your data instead of using NCA. However, concentration data over a sufficiently long period
will also be a pre-requisite for this.
4) Exclusion of profiles should only be done if the respective criteria have been defined upfront or
if there is a clear proof for protocol deviation or non-compliance by the patients.
I hope this helps and wish you all the best,
Associate Scientific Director
Dep, of Pharmacokinetics
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