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Hi, I am interested in performing some modeling using the Target mediated Drug Disposition Concept. Mager et al, Gibiansky et al and Peter Grimm provided some good reviews on this topic. However the concentration of the drug I have is in terms of free + partially free. Can someone provide some comments, assumptions etc. or any reference to any research article that discussed on how to handle the data from a modeling perspective when only free+partially free concentrations are available.
Regards
Neil
-- Indranil Bhattacharya
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The following message was posted to: PharmPK
Neil,
I think, you need to specify what is "partially free", and then use TMDD equations to compute that particular quantity. This is often difficult to do because assay is very difficult, so people who run it cannot say precisely what is actually measured. If you provide more details what do you know about "partially free", we can discuss it further.
Thanks
Leonid
--
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
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Thanks Leonid. At this moment I am not really sure what is the partially free concentration. But what I expect is that the partially free are antibodies (drug) with one arm bound to the antigen (target for treatment) and the other arm is bound to antigen (target for assay).
Regards
Neil
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The following message was posted to: PharmPK
Neil,
You need either measurements or assumptions to proceed. One possible assumption is that elimination of the drug-target complex (what you called partially free) is relatively fast. Then you would always have more free drug that this complex, and it is less likely for this "partially free" to pick up another target rather than be eliminated. If this is true, you can treat "free + partially free" as "total" in standard equations and proceed as discussed in those references that you cited.
Another case is when "partially free" part is eliminated slowly, and thus, have high chance of pick up another target. Then you may need to start from the first principles, write down equations for all species (free, partially free, fully occupied), and try to solve for them. You will have many parameters, and with one measured concentration, it is likely to be over-parametrized.
You can get some information from in-vitro studies. For example, what is the binding constants of free drug to a target, and what is the binding constants of the "partially free" drug to this target? In the discussion above, I assumed that they are similar. If not, you may try to use it in deriving your equations.
From the practical prospective and in the absence of the additional information, I would start from option 1 (treat it as total) and see whether you can get reasonable fit.
Thanks
Leonid
--
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
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