- On 23 Jun 2000 at 20:33:16, "Tony Lee" (p2149z.-at-.hotmail.com) sent the message

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Dear All,

You will be highly appreciated if you could

provide me your opinions and information about

how to analyze the relationship between

administered doses and pharmacological effects

by certain types of expressions. I don't know whether

those equations for concentration-effect relationship

apply to the dose-effect relationship and under what

conditions if they apply. I am also interested in

the interspecies scaling for PD parameters or

parameters from above dose-effect analysis. Will

the power exponent of 0.7 applys too?

Tony Lee

Email: p2149z.-a-.hotmail.com - On 25 Jun 2000 at 20:57:45, Nick Holford (n.holford.-at-.auckland.ac.nz) sent the message

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"Tony Lee (by way of David Bourne )" wrote:

> how to analyze the relationship between

> administered doses and pharmacological effects

> by certain types of expressions. I don't know whether

> those equations for concentration-effect relationship

> apply to the dose-effect relationship and under what

> conditions if they apply.

There is really no difference between dose and conc-effect models. You just

have to assume that conc has a constant value proportional to the dose (or

dose rate). If dose rate is constant then you can assume conc is dose

rate/clearance and model the effects as a function of average steady state

conc. You dont have to know the clearance. You can assume a nominal value of 1.

C=DoseRate/Clearance

If you want to describe a delay in onset of drug effect then the effect

compartment model is easily applied:

Ce(t) = DoseRate/Clearance*(1-exp(-Keq*t))

where Keq=ln(2)/Teq and Teq is the equilibration half-time.

> I am also interested in

> the interspecies scaling for PD parameters or

> parameters from above dose-effect analysis. Will

> the power exponent of 0.7 applys too?

PD parameters that describe functional properties of body e.g. cardiac

output, can be expected to scale with an allometric exponent of 3/4 (the

theory predicts this fraction; you can of course use 0.75 but not 0.7!)

PD parameters reflecting concentration sensitivity (e.g. EC50) are not

expected to scale with body size.

--

Nick Holford, Dept Pharmacology & Clinical Pharmacology

University of Auckland, Private Bag 92019, Auckland, New Zealand

email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556

http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm - On 29 Jun 2000 at 18:26:17, Jeff Wald (jwald.-at-.pharsight.com) sent the message

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One small addition to Nick's note: Whereas we do not expect parameters

like IC50's

to scale with body size, we oftentimes see that they scale with interspecies

differences in drug receptor binding (...of course accounting for

differences in

free drug concentrations).Some other PD effects which are mediated via

turnover (e.g., indirect response

models) can also be scaled between species when the constitutive turnover

kinetics

of the substrate being measured is known.

Regards, Jeff

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