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[Two replies - db]
Date: Thu, 30 Dec 1999 01:52:17 -0700 (MST)
X-Sender: ml11439.at.pop.goodnet.com
To: PharmPK.-at-.boomer.org
From: ml11439.aaa.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK Re: Statistical description of tmax
Hello Osama,
Regarding FDA Bioequivalence [the -20%/+25% rule]
I visited the FDA web site and read the FDA orange book and took
some notes. According to the FDA orange book, the FDA considers drugs
to bioequivalent if :
1) The rate and extent of absorption of the test drug to not differ
significantly from that of the reference drug.
2) The extent of absorption of the test drug does not differ significantly
from that of the reference drug and the difference from the reference drug
in the rate of absorption is intentional, is reflected in the proposed
labeling of the test drug, and is not essential to the attainment of
effective body concentrations and is considered medically insignificant
for the drug.
Statistical Criteria for Bioeqivalence
Bioequivalence of the test and reference drugs involves equivalence with
respect to the extent and rate of absorption. AUC (extent) and Cmax (rate)
are log-transformed for parametric statistical analysis where 90% confidence
intervals are computed for the mean of each log transformed parameter. The
90% confidence interval must be within 0.8 and 1.25 times that of the mean
of the reference drug. This is the -20%/+25% rule which means that if the
mean log-transformed parameter is close to -20% or +25% of the mean of the
log-transformed reference drug parameter, then the confidence limits are
likely to fall outside this range, and the test drug will not be bioequiva-
lent. Since the 90% confidence interval is two tailed, if it is within 0.8-
1.25 times the reference mean, there is only a 5% chance that the test drug
mean violates the -20%/+25% rule and might not be bioequivalent.
Evidently, other pharmacokinetic parameters reflecting extent and rate
of absorption may be used as implied by the terms "bioequivalence parameters
such as AUC or Cmax".
Therapeutic Equvalence verus Bioequivalence
The FDA classifies drugs as "therapeutically equivalent" if:
1) They are approved as safe and effective
2) They are pharmaceutical equivalents (same active ingredient)
3) They are "bioequivalent"
4) They are adequately labeled
5) They are manufactured with Current Good Manufacturing Practice
Mike Leibold, PharmD, RPh
ML11439.-at-.goodnet.com
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X-Sender: flerner.aaa.mail.intramed.net.ar
Date: Thu, 30 Dec 1999 08:21:55 -0300
To: PharmPK.-at-.boomer.org
From: Federico Ezequiel Lerner
Subject: Re: PharmPK Re: Statistical description of tmax
Dear all
For several kinetics parameters of some drugs is imposible to have log
normal distribution the example of that is drugs with different metabolic
pathway as fluoxetin that shows two kind of populations. so parametric
analyses is not appropriate.
Regards and best wishes for the new year
Federico Lerner
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Rate of the drug bioavailability is a function of time, not a constant
parameter. This function can be determined in a numerical and/or
analytical form. In our study (Durisova M. and Dedik L. Pharm. Res. 14,
1997, 860-864) we introduced a criterion which can be used for testing
equivalence of two rates of the drug bioavailability from two different drug
fromulations. The criterion is based on the weighting functions determined
in analytical forms.
With best wishes for the new year
Maria Durisova
Dr. Maria Durisova Ph.D.
Senior Research Worker
Scientific Secretary
Institute of Experimental Pharmacology
Slovak Academy of Sciences
http://kam.vm.stuba.sk/~dedik
SK-842 16 Bratislava
Slovak Republic
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)