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Hi all,
I have a question regarding the study design for PK study of HVDs (and for drugs with PK that are affected by food).
I am aware that for certain drugs that are highly variable (or affected by food), increasing the in-house confinement period prior to dosing (e.g. check-in on Day -2 instead of Day -1) and/or restrict the subjects diet, etc. can reduce the PK variability of the drug.
Are there any literatures that specifically (or incidentally) discussed that particular issue?
Thanks in advance.
Eric
Eric Siu, M.Sc., Ph.D.
Research Scientist, Clinical Pharmacology
Kendle Early Stage - Toronto
720 King Street West, 7th Floor
Toronto, ON, M5V 2T3
Canada
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Hi Eric.
I can't help thinking that there is another perspective on your question. Rather than creating a wholly artificial environment to do the study, it may be more helpful to run it as usual so that you get the variation in perspective. That would show what lies ahead in the development programme and even in the clinic. Wide variation could reflect a low mean bioavailability and not just a variable first pass effect, so I believe you need an IV dose in your design or at least to know what the established mean is for your population. By actually finding out the range and comparing it with your therapeutic ratio you get a perspective on the drug's potential to cause toxicity at the doses you will be forced to adopt to obtain efficacy in an acceptable proportion of patients. You might consider domperidone, an example of a molecule that stayed on the market for years despite an unusually low mean bioavailability of around 20% that gave room for a very wide range within individual patients and from tha
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Eric, Andrew
HVD's may be hydrotropes.
Amiodarone is a well studied example. (See, for example, Siddoway LA (2003), Amiodarone, Guidelines for use and monitoring, American Family Physician 68 (11): 2189-96).
In vivo, this variability is traced to the presence or relative absence of lipids and lipid soluble bile acids, which are related to the feed state.
Hydrotropes do associate with surfactants in vitro. This association is utilized in commercial/industrial cleaners. (See, for example, Handbook of Detergents, Part F, Chapter 14. Production of Hydrotropes, by Robert L . Burns, Edited by Uri Zoller and Paul Sosis, CRC Press 2009, Pages 247-251, eBook ISBN: 978-1-4200-1465-5).
This should be considered in the case of any wholly artificial environment to do the study.
Regards, Frank Bales, Ph.D. mailto: frankbales.aaa.msn.com
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Nice idea Frank. Can I ask how you would proceed? Assuming that lab tests show it is hydrotropic, which makes you do a high-fat vs a low-fat meal comparison in the clinic, how does it help you to decide whether the compound is viable?
Andrew
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Andrew,
The most problematical aspect of your question to answer is the nature of the lab tests to show that the compound is hydrotropic: hydrotropes do not form micelles. So there is no Critical Micelle Concentration of the compound to measure.
Two good hints as to hydrotropic character are the structural diagram, and the high apparent solubility.
If it is a hydrotrope, then it will form associations in water that give high measures for solubility but low measures for availability. The extent to which the hydrotrope can be released from the associations in water by the presence of lipids and lipid soluble bile acids points to the viability of the compound.
Hope this helps, Frank Bales, Ph.D. mailto: frankbales.-a-.msn.com
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