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Hi everyone:
I want to ask a question : Is Simcyp able to include tissue drug specific target binding for Vss calculation at PBPK individual tissue level ?
Because tissue specific target binding seems contribute a lot to my drug's tissue distribution besides nonspecific tissue lipid and protein binding
If Simcyp can , can you tell me how? if Simcyp cann't , is there any software can incorporate this tissue specific target binding into distribution volume calculation ?
Thanks and best regards.
Li zhang
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The following message was posted to: PharmPK
Dear Li Zhang
I think SimCyp software calculate and use kp values for different human
tissues (adipose, bone, gut, etc). It uses the equations described by
Rodgers and Rowland for moderate to strong bases, for acids, very weak
bases, neutrals and zwitterions. Take a look at:
- J Pharm Sci 2005, 94(6), 1259-1276
- J Pharm Sci 2006, 95(6), 1238-1257
- Pharm Res 2007, 24(5),918-933
- and Erratas for the publications in the J Pharm Sci
I simple used excel for my own calculations. Data for neutral lipid,
neutral phospholipid and tissue water residual fractional tissue
volumes, as well as tissue to plasma albumin ration and lipoprotein
ratio is described for rats and humans can be obtained from the referred
papers. These data is needed on the equations.
Best regards
Nuno Elvas Silva
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Dear Sila Nuno Elvas:
Thanks for your answer, it helps a lot.
But my drug besides binding to the neutral lipid, neutral phospholipid , tissue water and tissue protein, it still binds a lot to its receptors in tissue, and the receptors amount in tissue are substantial compared to its dose, which contribute a lot for the drug's tissue distribution . So I want to ask whether can add some drug receptors components in tissue in Simcyp software to predcit its distribution volume? or if there is any other software?
Thanks again.
Li
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The following message was posted to: PharmPK
Dear Li,
It may be more relevant to ask directly the SimCYP people about this question. To my experience, the available models for Vss are those from Poulain and Theil (2002) and Rodger and Rowland (2005, 2006, 2007). The equations are available in the papers published by the mentioned authors. They include binding to acidic phospholipids and nonspecific binding to proteins. Binding to targets is not included as the assumption is that drug concentration is in vast excess of target concentration so that binding to target does not affect pharmacokinetic parameters.
Kind Regards, Youssef.
Dr Youssef Hijazi
Drug Metabolism and Pharmacokinetics
Novartis Pharma AG
Basel, Switzerland
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Hi Li
As Youssef correctly explained binding to receptors isn't considered in Simcyp yet. However, if you know the tissue to plasma partition coefficient (e.g. from preclinical species) and if it isn't concentration dependent then you can incorporate it by overriding the predicted Kp value.
This year one of the Simcyp consortium wish-list items was the expansion of the Simulator to include modelling of biologics/therapeutic proteins and target mediated drug disposition. The consortium members voted for it so this will be available in version 12.
Regards
Masoud
Masoud Jamei, PhD, SMIEEE
Senior Scientific Advisor, Head of M&S
Honorary Lecturer, School of Medicine, University of Sheffield
Simcyp Limited
Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK
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Hi Masoud:
Thanks for your suggestion. While, my drug has a nonlinear tissue to plasma partition coefficient , and the nonlinear Kp was caused by the nonlinear target binding in tissue. I am looking forward to SimCyp version 12 for modeling tissue distribution with tissue target binding. When is it will be available? Is it able for both simulation and parameter estimation ?
Best regards.
Li
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Hi Li
Version 12 will be available in Spring 2012 (hope this isn't too long for you). And yes it is planned to expand the fitting capability to the TMDD module as it is available in other modules (e.g. DDI, ADAM, PBPK and PD (soon in version 11)).
Regards
Masoud
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Dear Li,
the current version of PK-Sim and MoBi are able to incorporate arbitrary binding processes at the sub-tissue level (you can choose whether the binding happens in plasma, interstitial fluid or in cells - in the protein PBPK models you could also add binding in the endosome of the vascular endothelial cells) into generic PBPK models for the whole range of species (mouse, rat, dog, minipig, monkey, cattle, and human) and populations PK-Sim offers. This allows you to deal with the specific binding processes that e.g. if you reach saturation concentations or when slow dissociation kinetics (low k_off values) lead to hysteresis. You are also able to implement more complex models for target mediated deposition if internalization and receptor-drug recovery play a relevant role.
As with the generic models, PBPK models extended by target mediated deposition or other specific binding processes can be used for simulation and the the numerical optimization routines allow you to run parameter identification jobs on all parameters including the generic ones and those added by the user. We have dedicated toolboxes for use of PK-Sim models from Matlab and R and you can for example run non-linear mixed-effect modeling routines on our PBPK models without the need to recode them in another environment (we had poster on this topic at this year's PAGE).
By the way: PK-Sim already has a Protein PBPK model incorporated that is capable of representing endosomal degradation of biologics as well as FcRn mediated salvage based on FcRn affinities. We presented a very nice application example for Albuferon that we did togehter with colleagues at Pfizer at this year's PAGE meeting. It demonstrates the possibility to even combine TMD with FcRn mediated processes. It is also an example where we directly used differential target expression levels to get more realistic tissue representations.
If you are interested in PK-Sim/MoBi you find more information under http://www.systems-biology.com
Academic, non-commercial use of our software platform is for free.
Best wishes
Joerg --
Dr. Joerg Lippert
Systems Biology & Computational Solutions
Bayer Technology Services GmbH
Leverkusen, 9115
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