- On 2 Jun 2006 at 13:03:37, Thenmozhi Arumugam (then_bio01.-at-.yahoo.co.in) sent the message

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Dear Members,

Greetings.

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

concentration?

I will be grateful if some one could elucidate me.

Regards, - On 2 Jun 2006 at 13:29:21, DDubins.-a-.allied-research.com sent the message

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The following message was posted to: PharmPK

Hello Thenmozhi,

> 1. Is it okay to calculate the new concentration by using this

method?

The method you are describing assumes mono-exponential decline of the

drug,

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

projected

concentrations without the pre-dose value.

> 2. If it is okay, will the regulatory accept this? And what is 't'

stands

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"

in the

formula would represent "time from pre-dose collection". Since the

pre-dose

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

this

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

primary analysis.

> 3. Is there is any guidelines talks about the calculation of new

concentration?

I haven't seen any guidelines regarding this. For drugs that have

endogenous levels in the bloodstream (e.g. hormones) baseline

normalization

may be appropriate. In this case, I would include a PK & stats

analysis on

both the raw and baseline-normalized data. Normalizing would be

performed

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

would

base BE on both the raw and baseline normalized ln-transformed PK

parameters.

If you are seeing many above-LLOQ pre-dose values, then you should

consider

a longer washout for the next study.

Hope this helps,

Dave Dubins

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