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hi all
the querry is how do we define a pharmacokinetic interaction? and a
pharmacologic interaction?
Is it necessary that a PK interaction will result in a Pharmacologic
interaction and /or vice versa!!!!
thanks in advance
neeraj
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The following message was posted to: PharmPK
Dear Neeraj,
It is easy if you can apply pharmacokinetic criteria: A (realistic)
view of the EMEA/FDA is usually that if a combination treatment is
bioequivalent in terms of Cmax and AUC, then there is no clinically
significant PK interaction. If the confidence intervals are outside the
80-125 % interval, but include unity (100 %), then an interaction is
not proven, while it is proven, if the CI are outside the 80-125 %
interval and do not include unity. The interval 70-143 % can be
discussed for Cmax.
These criteria apply not necessarily for drugs with a narrow
therapeutic index, but are quite useful.
It is harder with pharmacological criteria, here it depends on several
questions, but you should need a dose adjustment to call an interaction
clinically relevant. Except for narrow therapeutic index drugs a dose
adjustment is only possible using 50 % less (½ tablet) or 50 % more
drug (1½ tablet, in case of capsules 100 % more drug). Thus this calls
for a minimum of >25-ca50% change in mean/median efficacy or
tolerability. In case of drugs with a wide therapeutic index and ±high
variability (e.g. some Angiotensin II antagonists) you may even need
changes in the range of 100-200 % and more to consider a change as
clinically relevant, because such drugs are often dosed in the
saturation of the dose effect curve for efficacy with a low incidence
of adverse events.
Drugs with a narrow therapeutic index have most often formulations
which allow to adjust for smaller changes.
If you have enough data and a validated biomarker, you can try to model
which change in PK or PD might translate into a clinically relevant
change.
Kind regards,
Dietrich
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Mr.Neeraj,
Generally drug interactions occur with food or drug-drug interactions.
In drug-drug interactions it may occur at any of events like
pharmaceutical phase, pharmacokinetic phase andpharmacodynamicphase. In
pharmaceutical phase it leads to interaction in rate of release of drug
from another drug formulation and etc. In general pharmacokinetic
interactions can be due to the interaction at absorption, distribution
and metabolism phases of the anotherdrug.
Andpharmacodynamicinteractions will result due to interaction at
receptor level viz. agonist, antagonist properties, physiological
propertiesviz.onecan increase GI motility and another can reduce the
same and so many etc.
whencoming to your question about pharmacokinetic
andpharmacodynamicinteractions, all pharmacokinetic interactions need
not result in pharmacological interactions but we suppose there should
be acorreleationbetween plasma availability and drug response. So if
there is a relation between the drug concentrationvsresponseoraction,
then obviously it will.
I have explained very little info and I think our standard text books
of pharmacology can give u better idea.
Regards,
KANTHI KIRAN V.S. VARANASI
Sr. Research Scientist,
Pharmacokinetics Department,
Glenmark Pharmaceuticals LTD.
Glenmark Research Centre,
Plot No. A-607, T.T.C Industrial Area,
MIDC, Mahape,
NAVI MUMBAI-400709
INDIA.
Ph.: 91-22-55902491/92 ext 315
Fax: 91-22-55902318
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Mr. VARANASI
thank you very much for the respopnse. well what u have suggested is
right, however if one observes such interaction with not much change in
pharmacodynamics then how shall i proceed for finding the co-relation
between the Pk and the PD part. any suggestions from the group with
reference are welcome.
thanks
neeraj
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