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Dear sirs, do you think Cmax is the main parameter to decide
bioequivalence in BA and BE studies?
What would you think about an azithromycin BE study where AUC-ratio
accomplish the BE criteria but not Cmax-ratio (that is under 0.8)?
Thank you in advance
Neus Riba
Clinical Pharmacology
Hospital Clinic de Barcelona (Spain)
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The following message was posted to: PharmPK
Dear colleague,
bioequivalence of different formulations of the some drug substance
involves equivalence with respect to rate and extent of systemic drug
absorption.
How is the tmax trend? If only absorption profile (rate of absorption)
is changed, and not absorption extent, formulation with lower Cmax
shows higher tmax and similar AUC. If tmax is unchanged (mean tmax),
Cmax decrease is usually proportional to AUC decrease (that is to say
no changes of absorption profile/rate).
However, the typical way to answer your question is placed in the power
of statistical test you have employed in data analysis (typically
ANOVA).
Another way is the confidence interval approach [Schuirmann, D.J. A
comparison of the two one-sided tests procedure and the power approach
for assessing the equivalence of average bioavailability. J
Pharmacokinet Biopharm 15, 657-80 (1987) where the objective is to
determine if there are large differences (>20%) between mean parameters.
The procedure is:
1. Estimation of the 90% confidence limits for the sample means based
on Student's t-distribution of the data
2. The lower 90% confidence interval for the ratios of means cannot be
less than 0.80 and the upper 90% confidence interval for the ratios of
means cannot be grater than 120%.
Remember that for most drugs up to 20% difference in AUC or Cmax
between two formulations would have no clinical significance.
For a single-dose study ANOVA is usually performed on the
log-transformed AUC and Cmax. There should be no statistical
differences between the mean AUC and Cmax parameters for the test and
reference products. Based on log-transformed data, 90% of confidence
intervals about the means of AUC and Cmax values should not be less
than 0.8 (80%) and greater than 1.25 (125%).
Best Regards
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA
PO Box 328
Via ai Söi
CH - 6807 Taverne - Switzerland
e-mail: stefano.porzio.at.zambongroup.com
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The following message was posted to: PharmPK
Considering bioequivalence studies, the parameter Cmax is used to study
drug rate of absorption. AUC0-t and AUC0-inf are used to study extension
of drug absorption. These parameters are the accepted metrics for
bioequivalence decision, and all must be study.
According to NfG on the Investigation of Bioavailability and
Bioequivalence (CPMP/EWP/QWP/1401/98), the acceptance interval of
[80;125]% in certain cases may be wider (e.g. [70;133]%), once it is
justified in particular any safety or efficacy concerns for patients
switched between formulations.
Therefore, the clinic expert has to think about this matter for
azythromycin, i.e. if a suprabioavailability or infrabioavailability
within [70;133]%), for Cmax, doesn't compromise safety or efficacy of
the new generic product.
Best regards
Nuno Silva
Lisbon's School of Pharmacy
nmens.at.ff.ul.pt
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The following message was posted to: PharmPK
Dear Neus Riba,
The requirement of Cmax is more often mandatory to document the BA and
BE . Cmax signifies the rate at which the drug reaches into systemic
circulation and the rate is the parameter of the prime importance in
most , if not all, disease conditions as it determines the onset of
action to get the therapeutic benefit.
Azithromycin is an antibiotic drug here also rate is equally important
as it is going to define the time period for which the blood antibiotic
levels will remain above MIC of the succeptible bacteria and hence post
antibiotic effect, if any. If the Cmax differs significantly then it
would affect the rate of partitioning in tissues from the blood ( If we
consider blood as central compartment).Although while seeing
fundamentally in this case Cmax and the activity can not be correlated
very well as azithromycin accumulate heavily in tissues from there it
further deplet slowly.Natably, in application of azithromycin like in
treatment of local infections like H.Pylori the blood level would not
be the only concern as it would essentially be a local treatment in
part.
I hope this clarifies the issue in general and hope it would help u to
discuss the issue further specifically and precisely.
Kind Regards,
Pradeep S. Bhadauria
Research Scientist
RANBAXY RESEARCH LABORATORIES
INDIA.
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The following message was posted to: PharmPK
> Cmax signifies the rate at which the drug reaches into systemic
> circulation and the rate is the parameter of the prime importance in
> most , if not all, disease conditions as it determines the onset of
> action to get the therapeutic benefit.
The sigle quantity Cmax does not signify the rate at which the drug
reaches
the blood
circulation. The given rate is determined by a function of time, called
the
rate
of drug bioavailability. The rate of drug bioavailability provides
information about the bioavailability process at any point over a
course of
time.
> bioequivalence of different formulations of the some drug substance
> involves equivalence with respect to rate and extent of systemic drug
> absorption.
If one really wants to test similarity of two rates of drug
bioavailability
(as functions of time), she/he can used the criterion introduced in our
study
Durisová M, Dedík L. Pharm Res 1997; 14: 860-4.
The same criterion can also be used to test the similarity of two
rates of
drug
dissolution, as exemplified in our study
Dedík L, Durisová M. Comput Methods Programs Biomed 2002; 69: 49-55.
Regards,
Maria Durisova, PhD, DSc,
Head of Department of Pharmacokinetics
and Scientific Secretary
Institute of Experimental Pharmacology
Slovak Academy of Sciences
841 04 Bratislava 4
Slovak Republic
Phone/Fax: +421 2 54775928
http://www.uef.sav.sk/durisova.htm
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