Re: [NMusers] PD modeling question

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

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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
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---------- 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 Kin/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 Wed Jan 24 2007 - 12:40:24 EST