PharmPK Discussion - Selection of right in vivo dose in mouse for toxicity study

• On 8 Sep 2011 at 09:15:12, David Bourne (david.at.boomer.org) sent the message
  

  
  Dear All,
  
  I am working with a potential drug lead with activity in an asthma model The highest
  therapeutic dose is 3mg/kg. The dose selection was based on the maximum solubility of the
  compound in vehicle (3% DMSO in Saline). We discovered that the model is compromised if
  the DMSO percentage of the vehicle exceeds 6%. The compound was given twice daily (12hours
  apart) via intraperitoneal route and up to three days of treatment. Currently I intend to
  do pharmacokinetics and acute toxicity study of the compound in balb/c mice.
  
  I am facing some difficulty in selecting a suitable dose to convince my compound of
  interest is not toxic to the animals. Referring to OECD guidelines, the recommended
  starting dose is 5mg/kg, followed by 50, 300 and 2000 mg/kg. My dilemma is that the
  compound can only solubilize up to 10 mg/kg with the increase of DMSO% up to 10%.  At the
  moment, I intend to give treatment of 6 mg/kg daily up to 3 days and observe the animals
  for the next 14 days (acute toxicity study). My objective of the study is to convince the
  relevant authorities that the compound is a non toxic compound. As such I am wondering if
  the proposed treatment regime appropriate and acceptable. I would highly appreciate your
  expert opinion in this matter.
  
  Thank you for your precious time and thoughts.
  
  -
  Thanks for the post. Have a nice day
  
  Jonathan Lim Chee Woei
  Pharmacotherapeutic Unit,
  Department of Medicine,
  Faculty of Medicine and Health Sciences,
  Universiti Putra Malaysia,
  43400, Serdang, Malaysia.
  
  

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• On 8 Sep 2011 at 08:57:27, Abhijit Vichare (drvichare.at.yahoo.com) sent the message
  

  
  There are 2 options
  
  1. Can we select another vehicle and change the route of administration.
  For this we have to prove that the metabolic profile remains the same.
  Also by increasing the dose thereby increasing the exposure required for
  attributing to toxicity, we can prove the safety.
  
  2. Another question comes to my mind is If this drug is for asthma, why
  is it not by inhalation route?
  
  Regards,
  Abhijit Suresh Vichare
  
  

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• On 8 Sep 2011 at 10:57:25, chennamaneni rao (chennamanenir.aaa.yahoo.com) sent the message
  

  
  DMSO is not recommended for in-vivo studies and at least for repeat
  dosing. Select other acceptable formulation recipe (you can find several
  suggestions on pharmPK discussion list). You have to see what's the
  ED50? and exposure (AUC) at that dose?
  
  Next critical thing, can you increase the dose at least 10-15 times of
  your ED50 (with a change in formulation) to see increase in exposure??
  
  Regards,
  Rao
  
  

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Copyright 1995-2011 David W. A. Bourne (david@boomer.org)