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Dear all,
I would like to get an idea of when correction for baseline plasma
concentration (in conjunction with calculation of Cmax, AUCt and
AUCinf) is relevant.
Anyone practicing baseline corrections and for what kind of substances?
Kind regards,
Johan
[Is the material endogenous? Diurnal variation can interfere with any
attempts at 'correction' - db]
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The following message was posted to: PharmPK
Hi,
I have experience with a non-compartmental analysis for a drug which
was administered repeatedly for several study occasions. For some
patients, there were measurable drug concentrations from the previous
occasion, prior to dosing. Apparently, the washout period was too
short. Obviously, this prior concentration will influence your AUC
after a second dose (although a very low prior concentration might
have a negligible influence). It was chosen to estimate the resulting
AUC from this tail concentration, and to correct the AUC for the
subsequent study occasion for this.
For endogenous plasma concentrations you could think of enoxaparin,
which is measured indirectly via the anti-Xa concentration. Diurnal
variation of anti-Xa is limited. There are examples in which a
baseline fixed effect with between subject variability was implemented
for the baseline Anti-Xa concentrations, for instance:
1) Schoemaker et al., Br J Clin Pharmacol. 1996 Sep;42(3):283-90.
2) Green et al, Br J Clin Pharmacol. 2005 Mar;59(3):281-90.
Cheers,
Coen
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The following message was posted to: PharmPK
Johan,
I guess the first question is why you have pre-dose levels of your
drug. Are they due to previous doses or is it an endogenous compound?
I'd strongly recommend that you consider a modeling approach to your
data. If your pre-dose measurements are due to previous doses, a PK
model will take that into account and provides a better estimation of
the parameters. If it is due to baseline levels of an endogenous
substance, you may take that into account, when buildling your model.
The advantage here would be that (depending n the quality of your
data) you might be able to take into account the natural changes in
the substance. In any case, a PK model is much more informative and
offers several advantages compared to a simple Cmax/AUC estimation. At
a minimum, you may use the model to simulate future studies and
predict what might happen at other doses.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
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Dear Johan,
Two possibly useful papers including discussion for issues about
endogenous substances in PK and Bioequivalence studies:
1. Open questions on bioequivalence: some problems and some
solutions. Marzo A. Pharmacol Res. 1999 Oct;40(4):357-68.
2. Open questions on bioequivalence: an updated reappraisal.
Marzo A. Curr Clin Pharmacol. 2007 May;2(2):179-89. Review.
Kind regards
Stefano
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