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The following message was posted to: PharmPK
Dear Sergio Morales,
according to current EU guidelines multiple dose studies are still
mandatory. You will find the relevant documents at the links below:
http://www.emea.eu.int/pdfs/human/qwp/060496en.pdf
http://www.emea.eu.int/pdfs/human/ewp/140198en.pdf
http://www.emea.eu.int/pdfs/human/ewp/028096en.pdf
The main problem with enteric coated products is the high inter- (and
more important intra-) subject variability in gastric transit times.
You should carefully plan your sampling schedule. With voltaren (and
any other DL diclofenac product I have seen) it is very common - even
in replicate design studies - to see in the some subject a Tmax on one
occasion at 3 hours and on the next occasion at 12 hours. This does not
reflect variability in the rate of absorption - which is the product
characteristic we want to compare in a BE study - but only variability
in gastric transit. If you have not enough samples harvested during the
first 16 hours, you will end up with poorly defined Cmax/Tmax and high
variability. And even if you have enough time points, you still have to
deal with the variability in Tmax. One suggestion (originating from the
Central Laboratory of German Pharmacists) is to use Tmax minus Tlag as
the relevant rate parameter.
Good look
Helmut
Helmut Schütz Biokinet GmbH / Dept Biostatistics
Neubaugasse 36/11 Nattergasse 4
A-1070 Vienna/Austria A-1170 Vienna/Austria
tel/fax +43 1 9713935 tel +43 1 4856969 62
no cell phone ;-) fax +43 1 4856969 90
http://www.goldmark.org/netrants/no-word/attach.html
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In addition to the intra and inter individual gastric motily variation
Diclofenac undergoes extensive first pass metabolism, which would give
additional cause to variation
Dr Prashant
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The following message was posted to: PharmPK
Dear Dr Prahant,
yes, diclofenac undergoes extensive first pass metabolism, but I also
think that DR formulations of diclofenac are indeed highly variable
drug products (and diclofenac not a highly variable drug) since:
iv (ss) 5.62 (1)
solution (sd) 7.47 (1)
effervescent tablet (sd) 11.22 (1)
immediate relase (sd) 12.00 (4)
delayed release (ss) 13.14 (1)
suppository (sd) 14.64 (4)
oral suspension (sd) 17.61 (1)
controlled relase (sd) 20.22 (2)
delayed relase (sd) 22.10 (4)
dermal (sd) 32.70 (1)
sd=single dose ss=steady state
intra individual CV% for AUC (geometric mean of n studies)
The oral solution is very close to the iv route, and also the rectal
application shows a much lower CV as the delayed release formulations.
Again, we see the reduction of CV in steady state. It should also be
noted, that CVs especially in some of the DR studies were much higher.
Regards,
Helmut
Helmut Schütz Biokinet GmbH / Dept Biostatistics
Neubaugasse 36/11 Nattergasse 4
A-1070 Vienna/Austria A-1170 Vienna/Austria
tel/fax +43 1 9713935 tel +43 1 4856969 62
no cell phone ;-) fax +43 1 4856969 90
http://www.goldmark.org/netrants/no-word/attach.html
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