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he following message was posted to: PharmPK
Dear Group!
Since some of use have to deal with SHAM (Shape, Height, Area, Moment)
[(c) by Nick] aka NCA in a regulatory environment I want to initiate a
little survey.
The questions is simple:
How do you define Cmin in steady state (NCA only)?
Options (you may others if you want):
1. The minimum concentration within the dosing interval (used by all PK
software I know as the default).
2. The pre-dose concentration.
3. The concentration at the end of the dosing interval (WHO's and EMA's
definition).
4. The minimum concentration within time of administration and Tmax.
#1 gives a 50% probability for the time point of Cmin at t=0 and t=tau
due to random fluctuations. Any statistical location parameter will come
up with tau/2, a value which does not exist in the entire dataset.
Now for my personal preference: at least if a lag-time comes into play
I would opt for #4.
Best regards,
Helmut
--
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
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The following message was posted to: PharmPK
Dear Helmut,
In our practice we use for Cmin as per definition #1 because of possible lag-time in the release of the active ingredient.
For some special requests we define in the protocol also the Ctrough which the concentration measured at the end of the dosing interval (tau).
Some will like this parameter to be determined experimentally for reason of drug therapeutic monitoring.
We use the pre-dose concentrations for testing the achievement of the steady-state.
I hope this helps.
radu
Radu D. Pop
Pharma Medica Research Inc.
6100 Belgrave Road, Mississauga, Ontario, Canada
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Dear Helmut:
It is usually taken as the end-of-interval or the pre-dose concentration, using a 1 compartment model. However, if you are really concerned about the minimum concentration in a dose interval, it is usually achieved at a very short time after either an IV infusion or an oral dose. In both cases a short time is required until the rate of input into the central (serum) compartment becomes enough to start raising the serum concentration. This is usually best seen after either an oral or an IM dose, rather than an IV dose. It is especially seen in models having at least one peripheral compartment.
The same is true of concentrations or amounts in a peripheral compartment after an oral, IM, or an IV dose. Once again, the true minimum occurs very shortly after the input into the oral or the serum compartment.
You can see this with simulation studies.
Very best regards,
Roger Jelliffe
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Dear Helmet,
very nice discussion.
The questions is simple:
How do you define Cmin in steady state (NCA only)?
Options (you may others if you want):
1. The minimum concentration within the dosing interval (used by all PK
software I know as the default).
According to me 1st option will be more suitable answer for the question.
regards,,
venkatesan
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Dear Roger:
We normally we consider Cmin as a pre-dose plasma concentrations when steady state conditions are established. In reality one ca get the following situations:
1. C(trough) = pre-dose trough concentrations.
2. C(tau) = concentrations at the end of dose interval and
3. C(absolute) = absolute minimum concentratins during the dose interval.
I have encountered example of each case during the course of drug development. Hope thse comments will expand further discussion on Cmin.
Aziz Karim
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