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Dear all,
After withdrawal of Ketoconazole from the market we need to select another CYP3A4/P-gp inhibitor for
an interaction study. According to FDA and EMA guidelines Itraconazole seems to be a good
substitute. Have any of you used Itraconalzole in a clinical drug-drug interaction study? If yes, at
which dose and duration of treatment?
Any suggestion on other CYP3A4/P-gp inhibitors are more than welcome
Thanks a lot
Kind regards
Mirco
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To all:
This was brought up yesterday at a Delaware Valley Drug Metabolism Discussion Group meeting
(www.dvdmdg.org). While I don't have a recommendation, if we have to make a change, I would
recommend trying to find a suitable BCS Class 1 compound. I remember the issues around the
differences in phenotyping 3A with midazolam (Class 1) and erythromycin (Class 3). While a good
antifungal, itraconazole has a whole range of PK "challenges" (see the G&G PK list) that might
confound its use in an interaction study.
Chris Kemper
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Interesting conversation, in some of the experiments we carried out Itraconazole was more potent
inhibitor than Ketoconazole. Itraconazole is more specific towards CYP3A4 than Ketoconazole (AAPS
posters in 1992-1995). The major drawback itraconazole is its erratic bioavailability. You can get
around this bioavaialibility issues by dissolving itraconazole in tartatic acid and dose to get
consistent bioavailability and antifungal results.
FDA website provides Ki values for Ketoconazole (0.0037-0.18 uM) and Itraconazole (0.27-2.3 uM), not
sure what methoodology was employed. whether solubility issues were addressed in determining the Ki
values otherwise IMHO these values should be otherway round with low Ki values for Itraconazole.
We also have to keep in mind Ketoconazole apart from inhibiting CYP3A4/5 mediated pathways it also
greatly influence P-gp. These factors needs to be kept in mind when selecting a ketoconazole
substitute.
Coming to the issue of selecting an alternative to ketoconazole we may have to pick inhibitor drug
that comes close to Ki or IC50 values of Ketoconazole. Going by my memory Itraconazole solutions,
Ritonovir (0.17 uM), Norethindrone (mechanism based inactivation)or statins (high Ki values) would
be logical choices.
Hope this helps to initiate the broader discussion.
Prasad NV Tata, Ph.D., FCP
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Micro
One clarification to be made on your comment. You stated that ketoconazole is withdrawn from the
market. Is it the EU market you are referring to or the US or both? Ketoconazole is still used to
treat in the US although the prescribability may be low compared to itraconazole.
Manish Issar, Ph.D
Assistant Professor of Pharmacology
Western University of Health Sciences
College of Osteopathic Medicine of the Pacific
Pomona, CA 91766
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