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The following message was posted to: PharmPK
My name is victor and I have questions about the inhibitory Emax model
1) what is the difference between direct and indirect inhibitory Emax
model?
2) Considering an inhibitory effect. In the absence of any inhibitor
my effect would be 100%, then I start to increase the conc. of
inhibitor, but the max inhibition I can get is 40%. My Imax will be
40% or 60% (100-40)?
Sincerely
--
Whocely Victor de Castro
Graduate Student
Department of Pharmaceutics
University of Florida
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The following message was posted to: PharmPK
Victor,
The terminology 'direct' and 'indirect' is not very helpful for
understanding pharmacodynamics.
I think it is clearer to distinguish immediate and delayed effects
with respect to concentrations predicted by pharmacokinetic models
e.g. in the central compartment. Delayed effects may be due to slow
offset of binding to receptors (e.g. digoxin), distribution to the
site of action (e.g. thiopentone) and turnover of a physiological
mediator (e.g. warfarin). Any one or all of these mechanisms may
contribute to delayed effects. In earlier, less precise, terminology
the immediate effects were considered 'direct' while delayed effects
due to physiological turnover where considered 'indirect'.
To answer your second question it is helpful to distinguish between
the observed response (which may be seen in the absence of drug e.g.
in your example you say the response has a value of 100%) and the
effect of the drug to change the response. If the effect of the drug
is to reduce the response from 100% to 40% then the maximum drug
effect is -60% i.e. Emax (or Imax).
Nick
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The following message was posted to: PharmPK
Dear Victor,
1. There is only one kind of 'inhibitory emax model', there are no
two
kinds - direct and indirect. Perhaps you are referring to indirect
response
models versus direct effect model. The indirect response models are
employed
to describe the effect of the drug on the process that leads to the
formation or degradation of a biological signal. Even in these indirect
response models, the 'pharmacodynamic effect' is described using a
stimulatory or inhibitory emax model. On similar lines, consider the
effect
compartment model. The pharmacodynamic effect for the effect compartment
model is still the emax model. The effect compartment model 'links' the
concentrations and pd effect.
2. The inhibitory emax model is: Response BasalResponse*(1-
imax*conc/(conc+ic50)).
Response is the biological signal
measured, basalresponse is the baseline (say 100), imax is the maximal
fractional effect (can be expressed as %), conc is the drug
concentration
and ic50 is the conc required for half-maximal effect. Now, in the
absence
of drug ie., conc=0 => Response=BasalResponse*(1)=100 ie., the
Response is
equal to the baseline (no inhibition). Now, let us go with your example,
where the drug causes the response to drop to 60 (from a baseline of
100).
Then, Response=60; 60=100*(1-imax*conc/(conc+ic50)); at this maximal
effect,
conc>>ic50, so 60=100*(1-imax); 1-imax=60/100 or 0.6; imax=0.4. Sorry
for
writing equations using text editor. Now, i think of response as what
you
measure directly (enzyme activity, blood pressure, creatinine, etc), and
effect is the difference between responses before and after drug
administration (ie., enzyme activity with drug minus baseline enzyme
activity or a ratio). When you say 'inhibition' you are referring to
'effect'. The choice of nomenclature 'response' and 'effect' are
entirely my
biases and they help me to be consistent. Others might have a
different take
on this.
Joga Gobburu
Pharmacometrics, OCPB, FDA
10903 New Hampshire Avenue, Building 21, Rm. 4524
Silver Spring, MD 20993-0002
Ph: 301-796-1534, Fax: 301-796-9738
email: jogarao.gobburu.-at-.fda.hhs.gov
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