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We are at the stage of screening various possible solid dosage
formulations to identify the best/optimal formulation for oral solid
dosing. The company we are working with insists that the in vivo
screening be done in dogs or primates while we would very much prefer
to do this in screening in rats. The CRO's concern is that, using
the small capsules for the rats, they cannot be confident of dose
uniformity and that the variability will be too high to be
acceptable. I understand their concern but at the same time using
higher species for screening purposes seems quite outlandish for me.
Anyone else out there have had experience in this issue? Am I just
being a miser or is going the dog/primate route the way to go?
thanks in advance!
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The dog /primate is definitely the way to go for a number of
reasons. Capsule dosing in rodents is pretty tricky and even if
successful, you will need quite a few to get a decent concentration -
time profile. Secondly, there will be inter-animal variation.
The larger species are easier to dose, multiple blood samples can be
collected from the same animal without compromising its blood volume
and the animals can be re-used after a suitable washout period.
These considerations should reduce the cost difference
substantially. Finally, one of these larger species will be the
second species used for safety testing and the data you get will be
of use to the toxicologist in choosing that species and its doses.
It is also provides the opportunity to examine the species
differences in metabolism which may impact on the future development
programme.
Best wishes
Ian.
E: Ismith1945.-at-.aol.com
T: +44 (0) 1606-301767
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Dear Tai Ly
I very much understand your point. I went through this comparison
while I was doing my Ph.D. Using the rat as an animal model is good
and bad. It is good to give the first evidence of drug absorption
and metabolism. Particularly, human and rat share some hepatic
metabolic enzyme similarities. However, the bad consequence in this
model is the dosage form behavior through out the gastrointestinal
tract. This includes the gastric size, gastric residence time (GRT),
gastric emptying time (GET), small intestine transit time (SITT), and
the length of the absorption window(s). Of course this animal model
will cost you much less than larger animals. On the other hand, the
dog as an animal model has more advantages over the rat. You can
control the dosing condition under fasted or fed, you can administer
the target dose with 250 ml of water to gastric volume that is not
much differ from human. GRT and SITT in dogs can give a good idea of
the GRT and SITT in human. This type of information can be obtained
by External Scntigraphy Imaging of radiolabeled dosage forms. This
type of information is extremely useful if your dosage form
performance is GRT and SITT dependent.
If I had the option, I would go with dogs.
Should you fell discussing this subject on the side, please do not
hesitate to e.mail me at: darwazn58.at.yahoo.com
Regards
Nabil
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Dear Tai Ly
I very much understand your point. I went through this comparison
while I was doing my Ph.D. Using the rat as an animal model is good
and bad. It is good to give the first evidence of drug absorption
and metabolism. Particularly, human and rat share some hepatic
metabolic enzyme similarities. However, the bad consequence in this
model is the dosage form behavior through out the gastrointestinal
tract. This includes the gastric size, gastric residence time (GRT),
gastric emptying time (GET), small intestine transit time (SITT), and
the length of the absorption window(s). Of course this animal model
will cost you much less than larger animals. On the other hand, the
dog as an animal model has more advantages over the rat. You can
control the dosing condition under fasted or fed, you can administer
the target dose with 250 ml of water to gastric volume that is not
much differ from human. GRT and SITT in dogs can give a good idea of
the GRT and SITT in human. This type of information can be obtained
by External Scntigraphy Imaging of radiolabeled dosage forms. This
type of information is extremely useful if your dosage form
performance is GRT and SITT dependent.
If I had the option, I would go with dogs.
Should you fell discussing this subject on the side, please do not
hesitate to e.mail me at: darwazn58.aaa.yahoo.com
Regards
Nabil
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The following message was posted to: PharmPK
Dear Tai Ly,
Definitively, the best way to predict oral bioavailability in human of a
formulated compound is to run experiments in humans!!!. In the best of
my knowledge, the ideal animal species, which predicts what happens in
human, does not exist. Prediction of the PK behaviour in humans depends
on the compound / project of interest and its is in case by case basis
that such or such animal species can be chosen as the most reliable for
the project.
In your case, if metabolism is not an issue and if the rate of
metabolism is similar for both rat and human using either microsomes or
S9 fraction, then your idea to screen formulations in rats in order to
select the most promising ones sounds good. At Oroxcell we have run
numbers of formulations and PK studies in rats using small capsules. The
use of small capsules in rats seemed for us to work very good. More
specifically, there were no inter-individual variations and we were able
to select for our sponsors the most suitable formulation prior to proof
the concept in larger animal species.
If you need more details, please do not hesitate to contact me
(jean.pachot.at.oroxcell.com)
Hope this may help you.
Jean
Jean PACHOT, President & CSO
Oroxcell SAS
www.oroxcell.com
Parc technologique Biocitech
102, Rte de Noisy
F-93230, Romainville
jean.pachot.aaa.oroxcell.com
Tel/ +33(0)1 41 83 72 21
Fax/ +33 (0)1 41 83 72 27
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)