PharmPK Discussion - CaCo2 Pg-p Strange Results

• On 4 Aug 2011 at 15:36:59, David Benziger (David.Benziger.-a-.cubist.com) sent the message
  

  
  We conducted a study in two parts to look at the effects of a
  poorly/nonabsorbed drug (dosed orally) on the transport of digoxin by
  Caco-2 cells.
  
  In part 1, positive and negative controls were fine.  Several
  concentrations of drug up to 0.2 mg/mL had no inhibitory effect of
  digoxin transport. Concentration of drug based on estimate of amount in
  the 250 ml GI volume suggest by FDA guidance.
  
  In part 2, we decided that a  two-fold increase in the oral dose might
  be necessary in the clinic.  So we examine concentrations of 0.5, 1 and
  2 mg/mL (higher doses had solubility and cell toxicity issues).  The
  results for the positive and negative controls were fine.  However, we
  observed an approximate 50% inhibition with our drug at all three
  concentrations.
  
  Any thought on an explanation for lack of dose response?
  
  How could we address this finding to minimize the potential for an in
  vivo DDI study down the road?
  
  Could we go to another cell line like MDCK?
  
  thanks
  
  

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• On 5 Aug 2011 at 07:09:29, Sagnik Chatterjee (sagnik.chatterjee.at.gmail.com) sent the message
  

  
  Dear David,
  Could it be because of the toxicity issues, so the cells are actually
  dying, rather than effective enough to transport, you can do a
  functionality / viability test for the cells, to check this.
  And also if the drug is not soluble at those concentrations in the
  medium, then also you can see these effects.
  Regards
  Sagnik
  
  

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• On 5 Aug 2011 at 09:18:22, "amrit paudel.aaa.gmail.com" (amrit.niper.aaa.gmail.com) sent the message
  

  
  Hi David,
  
  I suspect the role of several factors for this manifestation.
  What is the status of added drug with respect to the Pg-p binding
  potential. Although you wrote both the negative and positive controls
  were fine, Pg-p flux kinetics is to be explored extensively before
  making the judgement.
  
  There could be the physicochemical origin of this observation. The
  concentration dependent solution state drug-Digoxin interaction
  (chemical/functional) could be equally probable. It is worth having such
  data before proceeding for the Caco-2 experiments. Or salting out of
  digoxin in the GI condition due to the drug addition could also be
  possible.
  
  Thanks and Best Regards,
  
  Amrit
  
  

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