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As we all know that the guidelines says:
If the predose concentration is less than 5 percent of Cmax value in
that subject, the subject's data without any adjustments can be
included in all pharmacokinetic measurements and
calculations. We recommend that if the predose value is greater than
5 percent of Cmax, the
subject be dropped from all BE study evaluations.
But one of the sponsors, who visited us, suggested that if a pre-dose
concentration is detected, the subject's data can be included in the
statistical analysis, without adjustment, if it represents less than
5% of the Cmax value of the corresponding period. If it is greater
than 5% of the Cmax value, a calculation taking into account the
residual value and the elimination constant will be done for
calculation of new values.
(New concentration) = (Actual concentration) - (residual
concentration) x (exp (kel x t))
Here is my query:
1. Is it okay to calculate the new concentration by using this method?
2. If it is okay, will the regulatory accept this? And what is 't'
stands for in the formula.
3. Is there is any guidelines talks about the calculation of new
I will be grateful if some one could elucidate me.
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The following message was posted to: PharmPK
> 1. Is it okay to calculate the new concentration by using this
The method you are describing assumes mono-exponential decline of the
which may or may not be true. This would entirely depend upon the
elimination characteristics of the drug. If the drug has
multi-compartmental PK, this model would not properly predict the
concentrations without the pre-dose value.
> 2. If it is okay, will the regulatory accept this? And what is 't'
for in the formula.
I wouldn't imagine the FDA would accept this. The sponsor may have an
argument if the drug is a non-complicated single-compartment IR drug,
however I would argue that doing this is polluting the data. The "t"
formula would represent "time from pre-dose collection". Since the
sample is typically not taken right at dosing, you have to be careful if
you plan on using this sort of subtraction to start the clock when the
pre-dose sample was taken rather than at dosing. I would not perform
normalization for an FDA study, but rather follow their very clear
instructions to drop the subjects in question from the analysis. If a
sponsor insists on subtraction this way, I would include it as
supplementary information and leave the FDA-recommended approach as the
> 3. Is there is any guidelines talks about the calculation of new
I haven't seen any guidelines regarding this. For drugs that have
endogenous levels in the bloodstream (e.g. hormones) baseline
may be appropriate. In this case, I would include a PK & stats
both the raw and baseline-normalized data. Normalizing would be
by subtracting the pre-dose concentration from the entire curve, the
underlying assumption being that the hormone levels wouldn't fluctuate
significantly over the course of the sampling times. In this case I
base BE on both the raw and baseline normalized ln-transformed PK
If you are seeing many above-LLOQ pre-dose values, then you should
a longer washout for the next study.
Hope this helps,
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