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In doing a DDI study with Ketoconazole, literature suggest several options.
2 days, 4-5 days or 1 week treatment with Keto prior to co-administration
with the new chemical entity (NCE). Given that Keto is at steady-state
after 2 days (t1/2 = 8 hrs) and given that it can cause QT prolongation (a
safety concern), in addition to higher cost of longer keto administration,
can you think of any reason why some investigators administer Keto for
longer than 2 days?
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You have raised a very pertinent point because in my view drug interaction
studies with ketoconazole are critical and should be done very early in drug
development. I normally recommend ketoconazole dose of 200 mg BID for five
days. With this dose one can achieve average plasma concentrations (Cavg) of
ketoconazole above IC50 values throughout the dosing interval.
I would like to seek opinions from others on pros and cons of 200 mg BID
vs. 400 mg QD dosing with ketoconazole in drug interaction studies. With 200
mg BID dosing, Cmax values will not as high as with the 400 mg QD dosing
[(AUC 0-24) with both dosing schedule would be similar]. One could argue
that higher Cmax values attained with 400 mg QD dosing would produce greater
inhibition in CYP 3A4 mediated metabolism. The opposite argument would be
that to maintain Cavg of ketoconazole above IC50 through the dosing interval
would be preferable and this would be better achievable with 200 mg BID
dosing. One also need to consider the tolerability and possible adverse
effects of the 200 mg BID vs. 400 mg QD dosing schedules with ketoconazole.
Any comments/opinions/advice on the above discussion will be highly
appreciated.
Aziz Karim
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[Two replies - db]
From: soraya.madani.at.pharma.novartis.com
Date: Thu, 27 Jun 2002 09:15:18 -0400
To: david.at.boomer.org
Subject: Re: PharmPK Drug interaction with Ketoconazole
Hello Dr. Karim:
I am not sure if based on very low Ki values ( 100-200 nM) of Keto for
CYP3A4, we are in any danger of falling below in either case of 400 QD or
200 bid. Hence, as far as inhibition is concerned both should work. Unless,
there are other concerns such as safety that can sway us one way versus
another. I would tend to go with what is recommended in the label. If I
recall correctly, it is 200-mg bid.
In any cas, thank for your response. It seems that in your practice to
administer Keto for 5 days vs. 2 days. Any scientific rationale for this
practice? Because, you are at SS after 2 days any ways.
Soraya
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From: joerg.herbst.-at-.syngenta.com
Date: Thu, 27 Jun 2002 16:59:17 +0200
To: david.at.boomer.org
Subject: Re: Drug interaction with Ketoconazole
Dear Soraya & Aziz,
I don't have experience with ketoconazole, but I am working with some other
triazoles used in agriculture (--> animal test data only!).
It is well-known, that triazoles (and the same is true for phenobarbitone)
have an inductive effect on xenobiotic metabolizing enzymes in liver. I
assume that this induction is not completed after 2 days or at least it is
not known whether or not it is completed after 2 days. Due to this inducing
effect it may take longer to reach a steady-state, as the induced enzymes
are involved in some metabolization steps of the triazole.
Regards
Jörg
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