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The following message was posted to: PharmPK
Dear all,
How the subjects with first measurable drug level as Cmax should be
treated with respect to different regulatory authorities?
Thanks a lot in advance for any useful information.
Regards,
Muhiyideen
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The following message was posted to: PharmPK
Dear Mohammed!
> How the subjects with first measurable drug level as Cmax should be
> treated with respect to different regulatory authorities?
FDA, Bioavailability and Bioequivalence Studies for Orally Administered
Drug ProductsaGeneral Considerations, Revision 1 (March 2003;
http://www.fda.gov/cder/guidance/5356fnl.pdf):
Section VI.D. First Point Cmax
The first point of a concentration-time curve in a BE study based on
blood and/or plasma measurements is sometimes the highest point, which
raises a question about the measurement of true Cmax because of
insufficient early sampling times. A carefully conducted pilot study may
avoid this problem. Collection of an early time point between 5 and 15
minutes after dosing followed by additional sample collections (e.g.,
two to five) in the first hour after dosing may be sufficient to assess
early peak concentrations. If this sampling approach is followed, we
recommend that data sets be considered adequate, even when the highest
observed concentration occurs at the first time point.
EMEA, Note for Guidance on the Investigation of Bioavailability and
Bioequivalence (July 2001;
http://www.emea.europa.eu/pdfs/human/qwp/140198enfin.pdf):
Section 3.1 Design
The sampling schedule should be planned to provide an adequate
estimation of Cmax [...]
EMEA, Guideline on the Investigation of Bioequivalence (Draft, July
2008; http://www.emea.europa.eu/pdfs/human/qwp/140198enrev1.pdf):
Section 4.1.4 Study Conduct / Sampling times
The sampling schedule should include frequent sampling around Cmax to
provide a reliable estimate of peak exposure. The sampling schedule
should be planned to avoid Cmax being the first point of a concentration
time curve.
For other countries see http://bebac.at/Guidelines.htm
Regards,
Helmut
-
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.at.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at
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Dear Helmut,
My question is not regarding first point Cmax. It is regarding the =20
first measurable point as Cmax (If we get nil concentration (BLOQ) for =20=
one or more points and directly the Cmax at the next point). Why I am =20=
asking this is, in the CDER Bioequivalence Review for Enalapril/HCTZ, =20=
Application No. 75-909;
=
http://www.fda.gov/cder/foi/anda/2001/75-909_Enalapril%20Maleate%20and%20H=
ydrochlorothiazide_Bioeqr.pdf
In page no. 9 under reviewer's comments, it is stated that,
"No subjects with zero hour drug level, 'first scheduled post-dose =20
time point as Cmax or first measurable drug concentration as Cmax'=94.
Please opine on the same.
Thanks and regards,
Muhiyideen=
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Dear Mr.Mohaideen,
I think you have the first measurable cocn is C max though it is not
occured as the first sampling point..
In quoted reference also, the reviewer had made three points
1. NO sero hour drug level, it means, the pre-dose concentration is
zero or below BLQ
2. No first schedule time post dose as C max, means, before T max
there are some sampling points.
3. No first measurable concn is C max, there is(are) some point(s)
which gives concn values , below C max and above BLQ.
In your case,
Even though, there is some sampling points before the T max, the
measureable concentrations is below BLQ and this poses one question
Your design of blood sampling points, If there is a large gap between
this observed T max and the preceded time, then regulator might
question.
Other members of the forum can also share their views.
T.R.Yegnaraman Manager-QA, Azidus Laboratories Ltd, 23, School Road,
Ratnamangalam, Vandalur Chennai - 600048, India
yegnaraman.aaa.azidus.com www.azidus.com
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The following message was posted to: PharmPK
I think it's important to recognize that the odds of taking a sample
right
at Cmax are vanishingly small. In other words, Cmax is almost never
any of
the observed values; rather, it is best calculated from a reasonable
mathematical model derived from the actual observations. The same
thinking
follows for Tmax.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
Folks,
Could not this phenomenon also mean that the compound has a very large
volume of distribution or a very rapid distribution phase? From my
small knowledge of anaesthetics that usally means it is highly
lipophilic, so if the compound is lipophilic it might be a genuine
event, whereas when the molecule is poorly fat soluble it is unlikely
to be so.
Andrew Sutton
Consultant in Clinical Pharmacology
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