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Regulatory authorities have recommended an interaction study between Drug X and
midazolam (CYP3A4 substrate).
Drug X undergoes extensive pre-systemic metabolism and only 1% of Dug X is
systemically available.
There is evidence that Drug X inhibits PgP.
There is no PK interaction between Drug X and donepezil; donepezil is a
substrate for CYP3A4.
Could we argue that an interaction study between Drug X and midazolam is not
required because we have shown that Drug X does not affect the pre-systemic
metabolism of donepezil?
Or would we have to show that midazolam and donepezil undergo similar gut and
liver metabolism?
If donepezil is predominately absorbed at a different gut region to midazolam,
could the extent of metabolism be different due to relative abundance of CYPP3A4
in gut?
Any thoughts appreciated.
Charlie Brindley
KinetAssist Limited
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Dear Charlie Brindley,
Drug X undergoes extensive pre-systemic metabolism following concurrent
administration with midazolam?
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What are the BCS classifications of your drug X and donepezil? If both are 1
(as is midazolam), you may have a case.
Christopher J. Kemper, Ph.D.
Pharma Navigators, LLC
DMPK/Bioanalytical Consulting
Alliance Management/Business Analysis
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In my understanding, midazolam is the most sensitive and specific substrate of
CYP3A4 to its conversion of 1-OH-midazolam. It is also a substrate for PgP. It
is best to perform at least one drug-drug interaction study (either alone or as
a part of a cocktail) with midazolam in any drug development process for a drug
that is cleared by metabolism. If drug X does not affect clearance of midazolam
then it is likely that it will not affect clearance of other drugs that are
metabolized by CYP 3A4. The opposite, however, is not necessarily the caset.
Aziz Karim
AzK Consulting, Inc.
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Charlie,
I think the extrapolation from Donepezil to Midazolam is not totally justified
yet. Details about the DDI study between Drug X and Donepezil would be useful.
Note that Donepezil might be a P-gp substrate according to this:
(PHARMACOGENETICS: Do CYP3A and ABCB1 genotypes influence the plasma
concentration and clinical outcome of donepezil treatment?
Laura Magliulo, Marja-Liisa Dahl, Grazia Lombardi, Silvia Fallarini, Laura Maria
Villa, Aldo Biolcati and Maria Gabriella Scordo)
Hence, depending on the role of P-gp in Donepezil absorption, distribution,
excretion,.... the results of the interaction with 3A4 might be diluted by
effects on P-gp. i.e. If your drug inhibits both P-gp and 3A4, then the results
from Donepezil are confounded. Midazolam will be a cleaner 3A4 substrate in that
case.
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Hi Charlie,
Where does your compound get metabolized intestine or liver or both?
If you can justify Donepezil is also a very sensitive CYP3A4 substrate
(substantial increase in exposures in the presence of other CYP3A4 inhbitors
like ketoconazole), may be you can argue. If your compound is exclusively
metabolized in the intestine wall, then you also may need to check whether
Donepezil also happen to metabolize in the intestinal wall like Midazolam..
Thanks
Ravi
Ravi Talluri Ph.D
GlenMark Pharmaceuticals, India
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Hello Charlie,
Based on the KETO interaction with donepezil, donepezil is not a sensitive
CYP3A4 substrate. Cmax and AUC are only increased 26%. Therefore the
regulatory agency is looking for a sensitive substrate interaction result.
You probably need to do a midazolam trial, or trial with another sensitive
CYP3A4 substrate.
Susan
Susan Shoaf
Dir. PK/PD
OPDC
Rockville, MD 20850
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Many thanks for all responders; it does appear that a midazolam interaction
study is required;
principally because, unlike midazolam, donepezil is a weakly sensitive CYP3A4
substrate and a PgP substrate.
Charlie Brindley
KinetAssist Limited
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