Re: [NMusers] PD modeling question

Ahmed,

In theory, Kin and Kout are the parameters of the system (biologic model)
and cannot change with drugs that are administered. If you
mechanistically believe that there is dual drug effect-- Kout (main
site) and Kin (secondary site-as you indicated), you'll have to built
it into your pharmacodynamic model..... You're correct that similar baseline
levels are leading to equal Kin/Kout ratios, but unless you've a strong
reason to believe that three systems had different Kin and Kout but the same
ratio- you cannot estimate these parameters separately. In essence, these
models should be driven by pharmacological properties rather than data
dependent reasoning.

To avoid the problems you're facing, which might due to limited data, you
can combine data from three drugs for analysis. You can maintain treatment
identity in the pharmacodynamic part of the model. The next step will be to
compare estimates of biologic as well as pharmacodynamic parameters with
that of the literature reported values.

Hope it helps,

Pravin



On 1/23/07, Ahmed Othman <aothm001_at_umaryland.edu> wrote:
>
> Hi Everyone,
>
> I am trying to model the PK/PD relationships for three drugs that inhibit
> the uptake of a neurotransmitter using indirect response models with
> inhibition of output. The three drugs differ significantly in the rates by
> which they elevate the neurotransmitter and the rates at which the levels
> return back to the baseline. This result in significant differences in the
> model estimates of K in and Kout for the three drugs despite the fact that
> the values of the baseline transmitter levels and consequently the Kin/K
> out ratios are equal for the three drugs.
>
> The three drugs are known to interact with the same transporter even
> though there are suggestions of differences in the mechanism of that
> interaction.
>
> Is the difference in the Kin among the drugs justified by the difference
> in the rate of elevation of the neurotransmitter? or is it contradictory
> to the theoretical basis of the model which defines K in as the rate
> constant for production of response (or the neurotransmitter here) and
> consequently it should be equal for the three drugs?
>
> Insights from the group and examples from the literature will be highly
> appreciated.
>
> Thanks
>
> Ahmed
>
>
> -----------------------------------------------------------------------------
>
> Ahmed Abdel-Fattah Othman
> Ph.D. Candidate
> Pharmacokinetics and Biopharmaceutics lab
> School of Pharmacy
> University of Maryland at Baltimore
> 20 Penn Street,HSF-2
> Baltimore, MD 21201
> Phone:(410)706-7388
> E-Mail:- aothm001_at_umaryland.edu
> -----------------------------------------------------------------------------
>
>
>

Received on Wed Jan 24 2007 - 00:39:09 EST