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hi All:
I am wondering about the value of conducting drug-drug interactions in
rats in predicting the DDI in humans. Let's say in the early
development of a compound where not much in-vitro metabolism data is
available and planning for the phase I as combination in cancer
patients with an approved drug. My question is; do we need to consider
the dose reduction based on the rat interaction data?
Looking forward for your input.
Sincerely,
vpokiri
[Enzyme differences between species might be more significant - db]
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Hi, Venkat:
Few things you may need to consider before using the rat model to
assess DDI potential in human:
Similarity of (1)serum protein binding, (2)major CYPs involved in the
metabolism, (3)Ki values, and (4) exposures between rat and human.
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Hi all,
In vivo DDI in rat does not predict human DDI due to metabolism
difference between the two species. The only way to predict DDI in
human is based on in vitro CYP and Pgp Ki values and Cmax . Depending
on data outcome FDA might require further in vivo clinical studies.
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>In vivo DDI in rat does not predict human DDI due to
>metabolism difference between the two species.
I couldn't agree more.
Andrew Somogyi and I once looked at the metabolism of the same drug to
2 different metabolites in Rat and Human microsomes, and used a panel
of known specific inhibitors side-by-side. The inhibition profile in
the rat microsomes was nothing like that seen in the human microsomes.
Regards,
David
David Foster, PhD
Lecturer
Sansom Institute
School of Pharmacy and Medical Sciences
Room P4-08
City East Campus
University of South Australia
Adelaide SA 5000
CRICOS Provider Number: 00121B
Email: david.foster.at.unisa.edu.au
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Dear Mr.Pokiri :
It's not advisable to conduct FTIM studies for oncology therapeutic
drugs either in stand alone or in combination form, complete
explaratory and regulatory stuides to be done in higher animal species
models, as well metabolism data to be established with effect of food -
without food .Radition studies also recommended for animal models.
Regards,
Korlapati V Rao
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How about the other way around?
In pharma drug discovery we screen for potential DDIs using in vitro
human CYPs... does that mean that when we do preclinical animal
studies we are free of potential DDIs in animals?
That has not been my experience... I'm curious what others think...
Thanks,
Dario
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The following message was posted to: PharmPK
In pharma drug discovery we want to predict human DDI. There are many
differences between species: enzymes are not the same and consequently
the metabolism pathways of one drug are not the same between animals
(e.g. rat) and human.
There is no CYP3A4 in the rat. And we do not know if ketoconazole, the
specific CYP3A4 inhibitor, specifically inhibits the corresponding CYP
in the rat... Then, a DDI study in the rat won't be useful to predict
a potential DDI in human... That does not mean that we do not see any
DDI in the rat. That dose mean that we do not know how to extrapolate
DDI from rat to human.
Hope that helps.
Francois BOUZOM
Head of non clinical modelling
Pharmacokinetics and Metabolism Center
TECHNOLOGIE SERVIER
25/27 rue Eugene Vignat
45000 ORLEANS (France)
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