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Dear all,
We are working on the PBPK modeling development of a compound with moderate permeability and low
PH-independent solubility using Simcyp. Our compound is primarily cleared by the metabolism via
CYP3A4. Lower dose of the compound (3.75mg) has about 10% higher bioavailability than higher dose
7.5mg, and bioavailability of 7.5mg is about another 10% higher than that of 15mg dose. Right now I
am planning to play around altering the segmental solubility along the GI tract of ADAM model
embedded in Simcyp. I am wondering that whether someone can share the experience of applying ADAM
model in Simcyp to simulate the absorption rate-limited phenomenon and/or dose-dependent change on
bioavailability.
Thanks very much.
Best regards,
Claire
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Dear Claire,
saturable 1st pass metabolism mediated by saturation of CYP3A could also be an explanation for this
finding.
Best regards, Uwe
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Have to disagree here! Saturable 1st pass metabolism mediated by saturation of CYP3A would lead to
higher F for higher doses. The opposite was observed.
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Just a few thoughts……..
Actually saturation of 1st pass at gut or liver should (with clearance being the same) result in
higher F at higher dose IF permeability and solubility are not limiting
Q: How was permeability determined/estimated? Is permeability in the system (assuming cellbased)
linear with increasing concentrations used?
Q: What is the solubility of the drug relative to the Dose(mg)/250(mL)-value
I would think that for simcyp to help on such sensitivity assessment you have to know biorelevant
dissolution and maybe allow for the drug to be absorbed via transporter and put a Km Vmax on that
see how that may work for you
Cheers
Hans
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Hi Claire
You are right to be mindful of solubility to be the cause of the
observed non-linearity but please bear in mind other possibilities
too. You mentioned that your compound has a moderate permeability this
may tell you that it is a substrate of an uptake transporter in the
gut and increasing dose saturate it so bioavailability drops. To be
able to investigate this possibility you need to do in vitro
permeability assay.
Anyway, you can use the segmental solubility entry boxes but please be
aware that using these them means you have already decided on the
solubility in each segment so the inter-individual variability caused
by pH (which is not relevant to your compound) and the level of bile
salt and their possible impacts on solubility and dissolution rates
can't be accounted for.
I guess some of the following articles may be useful:
http://www.ncbi.nlm.nih.gov/pubmed/24060671
http://dx.doi.org/10.1002/jps.23594 (open access)
http://www.sciencedirect.com/science/article/pii/S092809871300362X
http://www.ncbi.nlm.nih.gov/pubmed/22383166
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691459/ (freely available)
If you wish you can also contact Simcyp scientists
(support.at.simcyp.com) and I'm sure they will be happy to help.
Regards
Masoud
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Of course you are right. Sorry, I should have read the original message more carefully. Uwe
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Thanks a lot for everyone's input!
Hi Masoud,
We didn't test whether our compound is a substrate of an uptake transporter. We do know it is a
substrate of P-gp.
Actually I have i.v. (1mg), oral tablet (3.75, 7.5 and 15mg) and syrup (15mg) single dose PK. I
observed highest CL/F in 15mg syrup and dose-dependent decrease in CL/F for oral tablets from higher
to lower doses. Assuming the CLiv doesn't change, I think dose-dependent change in F could be one
possibility. Or at higher dose, P-gp mediated bile excretion also can also contribute to the
phenomenon assuming F does not change. Welcome any comments and critiques on my thoughts on this. I
am still struggling how to utilize my current data to test those possibilities.
Thanks a lot for the literature which seems very relevant to my project. I am discussing my problem
with some Simcyp scientists right now and they helped a lot. But we do think the discussion on
PharmPK also helps most of the time and that is why we also post the question here.
Thanks again for your help.
Hi Hans,
To your questions:
Q: How was permeability determined/estimated? Is permeability in the system (assuming cellbased)
linear with increasing concentrations used?
A: We don't have permeability determined by in vitro experiment. Right now the permeability used for
model development is based on in silico prediction.
Q: What is the solubility of the drug relative to the Dose(mg)/250(mL)-value
A: The solubility in water is more than 1000 fold lower than dose/250. The model using true water
solubility value doesn't produce reasonable results. Therefore I used simcyp library default value.
Thanks a lot for your thoughts again.
Hi Zuyu,
Thanks a lot for your disagreement. I definitely agree with you.
Best regards,
Claire
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Hi Claire,
Some information about the drug disposition will help verify the assumption that CL is
dose-independent. It is always tricky to explain changes in CL/F because it incorporates two
variables. So, are we sure nothing in the drug PK would suggest dose-dependent CL?
Still thinking solubility is the main suspect here.
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