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Hi:
I have to carry out a bioequivalence study involving a drug with 45
hours of half life. According GCP I should get samples until 3 half
lives, that is to say, about 5 to 6 days. Is this correct or in the
particular case of such long half lives, one could to obtain samples
until less than 3 half lives?
Thanking in advance,
Silvia Linares
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The FDA guidance stated: For a BE determination of an oral product with
a long half-life drug, a nonreplicate, single-dose, crossover study can
be conducted, provided an adequate washout period is used. ... sample
collection time should be adequate to ensure completion of
grastrointestinal transit (approximately 2 to 3 days) of the drug
product and absorption of the drug substance. ...For drugs that
demonstrate low intra-subject variability in distribution and clearance,
an AUC truncated at 72 hour (AUC0-72 hr) may be used in place of AUC0-t
or AUCi.
You can stop sampling at 72 hr after dosing.
Regards,
Bang Qian Xu, Ph.D.
Apotex Inc.
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The following message was posted to: PharmPK
Dear Silvia,
If you get samples inless than 3-4 T1/2; maybe your AUC0-last meassured
point is less that 80% of the extrapolated AUC to infinity and this is a
FDA rule.
Federico Lerner, MD
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Dear Dr. Lerner:
Could you please give me the website of FDA guidance regarding this AUC
rule? I was looking for this kind of guidance, but don't know where to
find it. Thank you very much.
Weijiang
Weijiang Zhang,
Department of Pharmaceutical and Biomedical Sciences College of Pharmacy
The University of Georgia
Athens, GA 30602
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http://www.fda.gov/cder/guidance/in ex.htm
Guidance for Industry (Bioavailability and Bioequivalence Studies for
Orally Administered Drug Products--General Considerations, October 2000)
Bang Qian Xu, Ph.D.
Apotex Inc.
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Dear all,
I would like to know is there a rule mentioned in guidances or
references concerning the concentrations of QC samples in relation to
methods validation for Bioequivalence studies. Should the
concentrations of quality control (QC) samples to be equal or to be
different from the concentrations of calibration standards?
I have one more request. May I ask you for sending me a copy of the
paper from Workshop/Conferance Report: Bioanalytivcal Method
Validation- A Revisit with a Decade of Progress, Pharmaceutical
Research, 2000, 17 (12),1551-1557 by V. P. Shah, K. K. Midha et al. I
will be very obliged, because I couldn't find the paper in our
libraries.
Thanks in advance!
Best regards,
Svetlana Stoyanova
Research Associate
Bioequvalence study Lab.
Sofia, Bulgaria
e-mail: SvetStoyanova.-at-.hotmail.com
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Dear Svetlana,
ICH guidelines for bio-analytical method validation say that you should
have atleast three QC concentrations covering the entire range of
concentration range-that is, QC concentration point at LOW (about 10-
20%), MIDDLE (about 50%) and HIGH (about 80%) concentration region of
the calibration curve. And its better if you take QC concentrations
different from that of your calibration concentrations, in the sense
that, by this way you will actually be testing the slope of your
calibration curve.
If your study sample concentrations exceed the highest calibration
point, conduct a parallellism or effect of dilution study to confirm
that there is no variation when you dilute ( to bring them into
calibration range) and analyse your high concentration samples.
Cheers!!
Kasiram
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The concentrations of quality control samples could be equal or different
from the concentration of calibration standards. In the FDA Guidance
(Bioanalytical Method Validation; May 2001), there are not rules concerning
this topic
(See attached file: 2000; 17(12); 1551-1557 (SHAH-VP).pdf)
[Again, the attachment is not included - contact the author directly
for a copy - some attachments could be placed on the PharmPK website
depending on copyright issues or a URL to the original could be
provided - db]
Gregorio Encina
Pharmacokinetics and Drug Metabolism Department
Laboratorios Dr. Esteve. S.A.
Avda Mare de Deu de Montserrat, 221
08041 Barcelona, Spain
gencina.at.esteve.es
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Is there someone who can pass information on the sample size
calculation of
a single-dose two-period cross-over bioequivalence study with
paroxetine?
Regards,
Michael Kummer
Pharmaforschung EuroConsult GmbH (PhEC)
Dr. Michael Kummer
Waxensteinstrasse 14
D-82467 Garmisch-Partenkirchen
email: michael.kummer.-at-.euroconsult.de
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Dear Dr. Kummer,
Based on intra-subject CV of 20-25% for AUC0-t and 25-30% for Cmax, you
will need 28-36 subject for 80% chance of concluding bioequivalence
(FDA regulations).
If your country of submission has "softer" regulations, e.g. there is
no requirement for 90% CI for Cmax to be between 80 and 125%, but just
for the T/R ratio, then a smaller sample may suffice.
Hope this helps.
With best regards,
Matthew Wasserman, B. Sc. Phm., M. Sc.
Associated Pharmacokineticist, Biometrics
Apotex Research Inc. - Biomedical Division
440 Garyray Dr, Toronto, Ontario, Canada M9L 1P7
Toll Free: 1-800-268-4623
Email: mwasserm.at.apotex.ca
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The following message was posted to: PharmPK
Hello,
My calculations are somewhat the same as Matthew Wasserman's based on
his assumptions: That is,
Exptected T/R = 0.95, Power = 80%, then if
intrasubject CV% = 30, and the 90% CI 80-125, n = 40.1 or 42
intrasubject CV% = 30, and point estimate only, n = 16.3 or 18
if intrasubject CV% = 25, and 90% CI 80-125 or point estimate, then
n = 28.3 or 30 or n
= 11.45 or 12
Of course, if the CV% <> 25 -30, the calculations will have to be
adjusted accordingly.
Best of Luck,
Edmond Edwards, Ph.D.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)