PharmPK Discussion - PK versus solubility in fed versus fasted

• On 18 Mar 2011 at 03:48:12, Vaibhav Sihorkar (vaibhav_s.aaa.aurigene.com) sent the message
  

  
  The following message was posted to: PharmPK
  
  Dear all,
  
  EMA has updated the "Questions & Answers: Positions on specific  questions addressed to the Pharmacokinetics Working Party"  EMA/618604/2000 Rev. 3" (dated 26 January 2011, published 14 March  2011).
  URL:
   http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/ 2009/09/WC500002963.pdf
  
  The interesting part is Section 11. "Clarification on the recommended  statistical method for the analysis of a bioequivalence study" (pages  21-32). Example data sets of a full replicate and a partial replicate  design as well as SAS code and results are given.
  
  If you use Phoenix/WinNonlin consider:
  
  3.3. Alternative computer programs
  SAS (version 9.1, SAS Institute Inc, NC) was used in the previous  computations. Results obtained by alternative, validated statistical  programs are also acceptable except spreadsheets because outputs of  spreadsheets are not suitable for secondary assessment.
  
  
  I've already posted a project-file containing the two data sets at  Pharsight's Extranet. Unless a coding matching EMA's results is  available, you cannot use Phoenix/WinNonlin in evaluating replicate  design studies for an application in the EU.
  
  Regards,
  Helmut
  
  -
  Ing. Helmut Schuetz
  BEBAC - Consultancy Services for
  Bioequivalence and Bioavailability Studies
  Neubaugasse 36/11
  1070 Vienna, Austria
  e-mail  helmut.schuetz.aaa.bebac.at
  web     http://bebac.at/
  contact http://bebac.at/Contact.htm
  forum   http://forum.bebac.at/
  
  I have been brain storming with few scientists towards a peculiar  situation. This compound in question (with moderate to high permeability  and moderate pgp efflux ratio) is nearly 4 times more soluble in fed  state (feSSIF) as compared to fasted state (FaSSIF) simulated intestinal  fluid (max solubility~0.1 mg/mL in FeSSIF). However, the POPK data of  this compound dosed (at same dose) in dogs is strikingly opposite to the  solubility data. The exposure is almost 20-30% more (with average  variance) in fasted state as compared to fed state at same dose.
  
  Is it possible that at fed state the marginal advantage of solubility is  getting nullified and the diffusion of compound (from delivery matrix)  may become rate limiting or could there be other explanations.  Appreciate, if PK scientific fraternity have views to explain this.
  
  regards
  
  Vaibhav
  
  --
  Vaibhav Sihorkar, Ph.D
  
  Pharmaceutical Development
  
  

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• On 18 Mar 2011 at 07:59:06, Frank Bales (frankbales.-at-.msn.com) sent the message
  

  
  Vaibhav,
   Marked increase in measured solubility in the feed state can indicate  hydrotropic behavior, similar to amiodarone (Cordarone).
  
  Regards,  Frank Bales, Ph.D.
  
  

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