Re: [NMusers] PD modeling question

Ahmed:

separate the biological system from what drug is doing to to the system
(pharmacodynamics).

If dX/dt=Kin-Kout . X governs the neurotransmitter levels at baseline,
then, in the presence of drug that inhibits reuptake dX/dt=Kin-Kout . X .
I(C), where I(C) is the pharmacodynamic function governing inhibition of
drug reuptake. Therefore, the apparent rate constant (Kout*) in presence of
drug is equal to Kout . I(C)
Kout*=Kout . I(C)
If you have different association and dissociation rates for each drug w.r.t.
interaction with the receptor, it needs to built into I(C). In presence of
drug, the Kout does not change but what changes is the apparent Kout
(Kout*)...(unless irreversible inhibition, feedback etc.)

So, if there some feedback depending on the extent of inhibition (extent of
elevation of neurotransmitter), only biology will help. That is what I
meant by building the model based on biology.

I don't know the exact system you're dealing with but to the extent I have
heard, I think, you should combine the data. The explanation for different
PD patterns should be built into the PD model and leave the biologic
component common for all drugs.

Pravin


On 1/24/07, Ahmed Othman <aothm001_at_umaryland.edu> wrote:
>
> Dear Pravin,
>
> The drugs increase the levels of the neurotransmitter by blocking the
> transporter responsible for its reuptake. However, it is believed that they
> have different rates of association and dissociation with that transporter
> which may be responsible for the significant differences in the rates of
> elevation and decline of the transmitter levels.
>
> I thought about modeling the three drugs together to force similar Kin and
> Kout values and get different drug related parameters as you have suggested
> but given the significant differences in the PD patterns, I did not think
> that I will achieve convergence with adequate fit for the three drugs.
> However, I am going to give it a try.
>
> I previously tried to Fix the Kin value for two of the drugs to the
> estimate achieved with the third, but it did not work and I got Kin/kout
> ratios far from baseline values
>
> 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
> -----------------------------------------------------------------------------
>
>
>
> *---------- Original Message -----------*
> From: "Pravin Jadhav" < pravinj_at_gmail.com>
> To: "Ahmed Othman" <aothm001_at_umaryland.edu>
> Cc: nmusers_at_globomaxnm.com
> Sent: Wed, 24 Jan 2007 00:39:09 -0500
> Subject: 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 K
> > in/Kout 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
> > >
> > -----------------------------------------------------------------------------
> >
> > >
> > >
>
>
> *------- End of Original Message -------*
>

Received on Thu Jan 25 2007 - 13:29:07 EST