PharmPK Discussion - Transporter in vitro studies vs clinical conc.

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On 29 Mar 2014 at 21:47:12, mailtaus (mailtaus.at.YAHOO.COM) sent the message


Dear all,
I have a question for the experts in the area regarding performance of in vitro studies with
transporters such substrate and inhibitory potential (IC50 determination) for transporters such as
pgp, BCRP, OATP1B1, OATP1B3 etc. My question is how to correlate the IC50 values from these in vitro
transfected cell line data to clinical concentrations. Whether we should consider free or total
concentrations in clinic. For CYP enzymes we consider total concentrations in clinic. But for
transporters which clinical concentrations should be considered. E.g. If in vitro OATP1B1 IC50 is 6
micromolar while clinical Cmax (total conc.) is 7 micromolar while free cmax is 2 nanomolar. How do
we interpret this data with respect to drug drug interaction potential.
Thanks in advance.

Tausif Ahmed
DMPK,
Piramal Enterprise s Ltd, Mumbai, India

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On 30 Mar 2014 at 16:00:40, Masoud Jamei (masoud.jamei.-a-.gmail.com) sent the message


Hi Tausif

Very good question and difficult to answer! Please see the following papers on P-gp IC50. As you can
see the inter-lab (and inter-system) variability can be huge, though you may find the proposed
solution in the second paper useful.

http://dmd.aspetjournals.org/content/41/7/1347.abstract

http://dmd.aspetjournals.org/content/41/7/1367.abstract

Regards
Masoud

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On 31 Mar 2014 at 10:02:43, ganesh mugundu (ganesh.mugundu.at.gmail.com) sent the message


Hi Tausif,

You would compare total Cmax concentration with the IC50 estimate. If total Cmax/IC50>0.1 (true for
your example), FDA guidance suggests the need for conduct of clinical DDI assessment.

Check Figure A4 for decision tree on  OATP1B1 DDI assessments
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf

Regards
Ganesh

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On 31 Mar 2014 at 18:32:04, Tobias Kanacher (tobias.kanacher.aaa.bayer.com) sent the message


Dear Tausif,

You might also take a look for an example how the problem can be solved for Pgp with the use of PBPK
modelling. See

Physiologically based pharmacokinetic modelli... [Br J Pharmacol. 2014] - PubMed - NCBI
http://www.ncbi.nlm.nih.gov/pubmed/?term=British+Journal+of+Pharmacology+(2014)+171+1043–1053+1043

Perhaps you can establish something similar with OATP.

Hope this might help you.

Tobias

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