PharmPK Discussion - IND for Biologics

• On 21 Aug 2011 at 16:45:19, Clinical Pharmacology (clinical.pharmacology.at.yahoo.com) sent the message
  

  
  New to the field of biologics and I wondered if anyone here can point me to where I can
  find more information on the pre-clinical PK/ADME work needed for filing an IND for
  biologics. How different is it from the IND filing data needed for small molecules? I
  tried to look for a guidance on the FDA website but was not very successful.
  
  Thanks
  

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• On 23 Aug 2011 at 15:00:25, Youssef Hijazi (youssef.hijazi1.aaa.gmail.com) sent the message
  

  
  Dear Clinical Pharmacology colleague,
  
  There is more guidance on preclinical safety requirement (ICH S6 ) than
  on ADME for biologics. However, any ADME activity that can be relevant
  to safety is useful. From experience, PKPD studies are highly useful.
  The characterization of PKPD relationship and using model-based approach
  for prediction of human dose (e.g. MABEL approach) is becoming a comon
  practice (the below reviews may be of help to you).
  With regards to drug metabolism and drug interactions, they are
  extensively studied for small molecules, however they are generally not
  required for proteins with some exceptions in case of biologics that can
  modulate cytokines which may have indirect effects on CYP450 expression.
  Some times we do tissue distribution studies of biologics in rodents
  using radiolabel to look for any accumulation in certain tissues and to
  interpret certain tox findings.
  In case of low molecular weights biologics with < 50 kDa renal exretion
  may be expected and determination of contribution of renal clearance to
  drug elimination may be warranted.
  As most biologics are given by IV and/or SC routes, assessment of SC
  bioavailability is desired before moving to clinics.
  Issues like immunogenicity, assay format and their implications on PK
  and PD should be sorted out.
  
  Hope this helps,
  
  Kind Regards, Youssef
  
  Youssef Hijazi, PhD. PharmD, member ACCP
  Associate Director Pharmacokinetics
  Micromet AG
  81477 Munich, Germany
  
  On setting the first dose in man: quantitating biotherapeutic
  drug-target binding through pharmacokinetic and pharmacodynamic models.
  Lowe PJ, Tannenbaum S, Wu K, Lloyd P, Sims J. Basic Clin Pharmacol
  Toxicol. 2010 Mar;106(3):195-209. Epub 2009 Dec 29. Review.
  
  On the anticipation of the human dose in first-in-man trials from
  preclinical and prior clinical information in early drug development.
  Lowe PJ, Hijazi Y, Luttringer O, Yin H, Sarangapani R, Howard D.
  Xenobiotica. 2007 Oct-Nov;37(10-11):1331-54. Review.
  
  

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• On 25 Aug 2011 at 17:54:15, krishna machavaram (machavaramk.-at-.gmail.com) sent the message
  

  
  Dear clinical pahrmacology colleague,
  
  There has been increased emphasis on CYP450-mediated biologics-small
  molecule interactions recently by regulatory authorities (such as US
  FDA) and scientific community. I think it is important to investigate
  the potential for drug-drug interactions caused by bilogics (i.e. via
  suppression of CYPs/transporters, etc) at the early satge of drug
  development as these interactions may have dosage labelling
  implications.
  
  Please find the reference below for more details.
  
  Huang SM et al., 2010, Clin Pharmacol Ther 87, 497-503.
  
  Hope this information is useful.
  
  All the best,
  
  Krishna
  
  

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