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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.
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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
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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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
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,
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