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Dear All,
We have come across an unusual query on BE study of ketoconazole
tablets (compared with Nizoral [jansenn]in 24 healthy volunteers, in a
cross over fashion). Our results show that our product is bioequivalent
to the innovator based on the current requirements of 90% confidence
intervals etc. However, the interindividual variability measured in
terms of %CV is about 5%[both for Cmax and AUC].
Now, the literature shows that ketoconazole has variable
pharmaciokinetics with high inter as well as intra individual
variability [most of the results show %CV of about 25-30%].
In that case how do we justify the very low inter individual
variability of ketoconazole in the volunteers of our study?
We think that it may be attributed to the standardised conditions [age,
food, similar health status of volunteers etc] during a BE study,and
the fact that the reported variability is mainly in the patients with
variety of fungal infections.I would be grateful if any one could
comment on this.
regards,
kaushal Prajapati
Torrent Pharmaceuticals limited.
Dear Mr. Prajapati,Back to the Top
Please first check whichwhich formula you are using to calculate your
interindividual variability and intraindividual variability. Are you
calculating for log-transformed data or untransformed data?
Regards,
Priti
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Dear Kaushal,
Nevertheless, its the practical data substantiated with evidences to
establish the validity of the study protocal and analytical study
method ( 21 CFR Part 11 compliance) will be what is required in your
case to justify your standpoint to regulatory authorities.
How much is the %CV in your product and refernec product
respectively.Is it comparable ??
Kind Regards,
Pradeep S. Bhadauria
RANBAXY RESEARCH LABORATORIES.
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Simply accept the fact that you have a better study. Harold.
Harold Boxenbaum, Ph.D.
Arishel Inc.
14621 Settlers Landing Way
North Potomac, MD 20878-4305
(P) 301-424-2806
(F) 301-424-8563
harold.-at-.arishel.com
www.arishel.com
Dear Pradeep,Back to the Top
The inter individual variability for the test formulation is 3.4% and
for the reference formulation it is 4.1%. We have tried to justify the
low variability based on the standardised study conditions and adequate
sample size of the study. We also found that the major variability
observed was in patients with different severity of fungal infections.
Could that form the basis of our justification? Also, most of those
were after multiple doses of the formulation. Can this help as
ketoconazole is shown to cause auto induction and saturable first pass
metabolism.
Regards,
Kaushal Prajapati
Corporate Quality Assurance
Torrent Pharmaceuticals Limited
--
Dear Priti,
The following formula is used to calculate the interindividual
variability for ketoconazole study :
Interindividual variability = SQRT ({Subject MSS - Residual MSS}/2)*100
Regards,
Kaushal Prajapati
Corporate Quality Assurance
Torrent Pharmaceuticals Limited
Dear Kaushal,Back to the Top
First of all authorities may not necessarily ask any justification for
this difference and most of the variability data documented in SBA or
any other literature is a an outcome of clinical trials on patients (
as you mentioned) wherin the disease related factors are also
contributory . As BE studies are done in healthy volunteers and its not
surprising if this dosenot corelate well with documented patient data.
I have come across few such cases of Highly variable drugs having
documented variability( %CV) of more than 60-70% but practically it
could not be corelated with BE data on healthy volunteer.Anyways, your
study was a fed or fasting study??
Hence you should simply recognise the fact that you have had a better
controlled study.
Reagrds,
Pradeep Bhadauria
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