- On 22 Jan 2003 at 16:30:42, "neus riba garcia" (nriba.at.medicina.ub.es) sent the message

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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) - On 23 Jan 2003 at 10:08:50, "Porzio, Stefano" (Stefano.Porzio.-a-.ZambonGroup.com) sent the message

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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 - On 23 Jan 2003 at 10:57:58, "Nuno Elvas Silva" (nmens.at.ff.ul.pt) sent the message

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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 - On 23 Jan 2003 at 19:36:31, (pradeepbhadauria.aaa.sify.com) sent the message

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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. - On 25 Jan 2003 at 10:18:27, "Durisova Maria" (exfamadu.aaa.savba.sk) sent the message

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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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