PharmPK Discussion - Olanzapine double peak

• On 12 Apr 2012 at 01:26:37, "Paliwal , Nishant" (nishant_paliwal.-at-.clinsys.com) sent the message
  

  
  Dear All
  
  I have received a query from the regulatory authorities regarding a
  bioequivalence study done by us for olanzapine 5mg oral tablets
  
  'we have done sample collection uptill 144 hr after oral dosing for the test
  and reference products. Cmax for the drug comes at 6hr . However it has reported
  a sudden dip at 12 hr after which the concentration rise again at 24 hr leading
  to a double peak in pk  profile. Olanzapine does not show any food effect so the
  a relationship of this to delay in gastric transit ruled out, there are no
  evidence or literature available to support the absorbtion window or pH effect
  to this . Can this be related to enterohepatic recirculation as olanzapine is
  highly gluronidated and the secretion along with bile can bring about the
  following effect.
  Kindly provide your valuable justification
  
  Nishant
  

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• On 12 Apr 2012 at 10:45:30, renu singh (singrenu.-at-.yahoo.com) sent the message
  

  
  Hi Nishant,
  
  There is a great likely hood that the double peak you have observed is due to
  enterohepatic recycling. A BDC study should help you to answer the querry.
  
  Best regards,
  Renu
  
  Renu S. Dhanikula, PhD
  Scientist, DMPK
  AstraZeneca R&D Montreal
  
  

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• On 16 Apr 2012 at 08:02:26, DRGUNA SAKARAN (drgunasakaran.-at-.gmail.com) sent the message
  

  
  Dear Mr. Nishant,
  
  Olanzapine obeys multicompartment kinetics with multiple peaks in the concentration-time
  profile suggesting either erratic absorption, enterohepatic and/or entero-enteric
  circulation.
  
  Olanzapine demonstrate a considerable first-pass effect, as shown by portal
  versus-systemic plasma measurements, as well as a noteworthy enterohepatic recirculation
  of biliary excreted metabolites.
  
  You can quote the following references and provide sound scientific justification for the
  double peaks observed in your bioequivalence study with Olanzapine.
  
  References:
  European Medicines Agency assessment report for Zypadhera, International nonproprietary
  name: Olanzapine. Procedure no. EMEA/H/C/000890. Doc.ref.: EMEA /608654/2008.
  
  Subha Rani et al., Pharmacokinetics of olanzapine in asian indians and comparison with
  other populations: Possibility of population diversity. Indian Drugs, 2002, vol. 39, no11,
  pp. 583-588.
  
  Thanks & Regards,
  Dr.S.Gunasakaran, MD
  Head - Clinical Research & Medical Affairs,
  Azidus Clinical Research Organization, India
  

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