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Dear all,
I would like to know if physiologically based PK models are used to estimate
drug concentrations at the site of action. I have read about different organs
being represented in such models but what about sites not normally used, e.g.,
adipose tissues or heart? Is such practice common when modeling data using PBPK
approach? References are highly appreciated.
Best regards,
BP
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The following message was posted to: PharmPK
BP,
PBPK can estimate tissue concentrations - intracellular and extracellular.
The bigger question is often "What/where is/are the site/s of action".
You can certainly build PBPK/PD models using predicted tissue
concentrations to see if they are better for modeling response than plasma
concentrations. But the tissue concentration is not necessarily the same
as that at the site(s) of action.
Best regards,
Walt
Walt Woltosz
Chairman and CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534
www.simulations-plus.com
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Dear Batul,
Edginton et al. published a paper on the use of PBPK modelling to
simulate the brain and effect concentration of propofol.
Reference: Edginton AN, Schmitt W, Willmann S. Application of
physiology-based pharmacokinetic and pharmacodynamic modeling to
individualized target-controlled propofol infusions. Adv Ther
2006;23(1):143-58.
Hope this help. Winnie
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Hi Batul
I couldn't fully understand your question. One of the main objectives of using
PBPK models is to get better understanding of the tissue/organ concentrations
(including the ones that you mentioned) which can be used to drive PD. You may
find the following references useful:
Rowland M, Peck C, and Tucker G (2011) Physiologically-Based Pharmacokinetics in
Drug Development and Regulatory Science. Annual Review of Pharmacology and
Toxicology 51:45-73.
Rostami-Hodjegan A (2012) Physiologically Based Pharmacokinetics Joined With In
Vitro-In Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems
Pharmacology. Clin Pharmacol Ther 92:50-61.
Regards
Masoud
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The following message was posted to: PharmPK
Dear Batul,
I agree with Walt on the importance of knowing the site of action and whether
the target is intra/extracellular. In addition, one should also be aware of the
limitations and assumptions involved in arriving at the tissue concentrations.
For example, many PBPK models use in silico methods employing logP, pKa, free
fraction and tissue compositions to calculate tissue partitioning coefficients.
These coefficients will determine the quality of tissue concentration
predictions. With no way to verify the accuracy of predictied partition
coefficients (even if they are able to predict the overall volume of
distribution), we can never be sure how well the predicted tissue concentrations
represent that in vivo. If your compound is a substrate for uptake transporters
and your target is intracellular, it gets even more complicated.
Regards,
Sheila Peters
--
R&I iMed DMPK
AstraZeneca R&D Moelndal
Pepperedsleden 1
43183 Moelndal
Sweden
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Dear Batul,
Sheila Peters is being too modest in her comments to you. She has recently
published a book on the application of PBPK models in the pharmaceutical
industry and presents in many lucid chapters a complete and interesting account
of the equations used in constructing these models. It is a very thorough
exposition on the subject for anyone interested in applying PBPK models.
I have purchased quite a few books on the subject in the past, but hers is the
most relevant for drug development and fills a necessary niche.
It only remains to say - you should find this book and form your own opinion.
It also remains to say, that I have no ties, financial or otherwise with the
author.
Best Wishes,
Edmond Edwards
[From 4 Apr 2012 - Physiologically-based
pharmacokinetic (PBPK) modeling by Sheila Peters, published by Wiley in March 2012.
http://www.wiley-vch.de/publish/en/books/bySubjectCH00/ISBN0-470-48406-3/?sIDj0nb9deln67nmjv14ejhfjern2
- db]
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