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The following message was posted to: PharmPK
A drug shows a decrease in Cmax and AUC on chronic PO
dosing.
(1) Besides autoinduction, can there be anything else
possibly going on?
(2) What is the best way to present the oral PK data
to represent autoinduction?
(3) Will in-vitro metabolizing enzyme induction
studies with the same drug help in narrowing down the
enzyme(s) responsible for the autoinduction?
(4) The drug in question is a prodrug. How will its
autoinduction affect its preclinical development?
I will appreciate receiving advise from PharmPK
members.
Regards
Ananda
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The following message was posted to: PharmPK
A drug shows a decrease in Cmax and AUC on chronic PO
dosing.
(1) Besides autoinduction, can there be anything else
possibly going on?
(2) What is the best way to present the oral PK data
to represent autoinduction?
(3) Will in-vitro metabolizing enzyme induction
studies with the same drug help in narrowing down the
enzyme(s) responsible for the autoinduction?
(4) The drug in question is a prodrug. How will its
autoinduction affect its preclinical development?
I will appreciate receiving advise from PharmPK
members.
Regards
Ananda
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The following message was posted to: PharmPK
Dear Ananda,
Before being able to answer your questions on the possibility of an
autoinduction, there are a few assumptions/questions one will need to
consider. You mention that after chronic p.o. administration of your
compound (a pro-drug) both Cmax and AUC are decreased. The first
question would be if the magnitude of the decrease is large enough to
be attributed to a real phenomenon and not the variability. What are
the ratios of Cmax and AUC for before and after treatment values? You
also state that your compound is a pro-drug. This could be of enormous
help. If autoinduction occurs, you expect to see more metabolite(s), in
this case the active compound, be built. Do you see increased Cmax/AUC
for the active compound over time? If the autoinduction also affects
the active compound, do you know what metabolites are made? And do you
see higher metabolite concentrations with time? The next step would be
to look further at the metabolizing enzymes. Are the metabolizing
enzymes of you drug known? If yes, are these enzymes known to be
inducible? It would also be interesting to have more information on
the time-course of the presumed induction: how fast do you see the
"induction" to start?
My own expertise has been with a potent auto-inducer, the antimalarial
compound artemisinin. I would suggest that you look at the literature
published on the pharmacokinetics of artemisinin. Several excellent
papers on the induction phenomenon as well as studies on what enzymes
are responsible/induced by artemisinin have recently been applied. I
believe these studies address the same question you rise in your mail.
> (1) Besides autoinduction, can there be anything else
> possibly going on?
The compound is administered orally. On has to realize that
bioavailability, and thus AUC or Cmax, can change due to other factors
than induction of hepatic enzymes. These factors could include
induction of pgp or CYP-450 enzymes in gut. Does the compound change
the physiological conditions in the gut environment, which might affect
its absorption?
> (2) What is the best way to present the oral PK data
> to represent autoinduction?
I am not quite sure if I understand the question. I guess you might
again want to look how people have presented data for artemisinin PK.
> (3) Will in-vitro metabolizing enzyme induction
> studies with the same drug help in narrowing down the
> enzyme(s) responsible for the autoinduction?
It is quite possible to do so and has already been done for a number of
compounds, again, including artemisinin.
> (4) The drug in question is a prodrug. How will its
> autoinduction affect its preclinical development?
I am afraid I do not have much experience of pre-clinical work. Several
types of preclinical studies, however, might help you determine the
cause of the decreased values of Cmax and AUC. You have already
mentioned in-vitro metabolizing enzyme studies. Others would include
in-situ perfusion of livers with subsequent check of the enzymatic
activity or iv dosings, if possible. Animal studies, however, require
that you first establish the relevant animal model since you might not
observe the same phenomenon due to enzymatic differences between
species.
Toufigh Gordi
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The following message was posted to: PharmPK
Dear Ananda,
You might also want to have a look at the PK literature on rifampicin,
which is another potent (and well-studied) autoinducer.
Best regards
Justin Wilkins
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