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Dear all,
I would like to use your advice regarding a preclinical data set with unusual values.
We have conducted a PK study in 3 doses (5, 20, 80 mg/kg) as a single oral dose in rats.
The dose changes 4 fold each time but the AUC was elevated more than 4 fold between the 5 and 20 mg doses (12 fold) and then linearly between the 20 and 80 mg doses (5 fold).
Is it considered a non-linear PK? What can be a reason for partial non linearity?
The compound has no intestinal efflux, its 99% bound to albumin and extensively excreted in the bile so I was aiming at saturation of metabolism but the return to linearity doesn't fit.
In addition when I use one compartment model (micro) to describe the data (best fits...) I get changes in Cl/F(57,19,15), V/F(120,70,180) and K10 (1.5, 2.6, 8.2) in the 5, 20 ,80 mg doses respectively...
Thank you,
Arik
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The following message was posted to: PharmPK
Dear Arik,
Such preclinical studies are mostly performed -for obvious reasons- with a minimum of animals (n in 2 to 5 range). With this in mind I would rate your results as borderline: they may be real, but they may also be due to plain variability (hypothesis 1). Extensive bilary excretion may lead to reabsorption and therefore increase variability, adding to the credibility of this hypothesis 1.
An alternative explanation could be a dual mechanism of clearance where one would have a lower capacity (e.g. bilary and some CYP-mediated with a lower capacity); this would be hypothesis 2. You might be able to give this hypothesis further support by fitting all data together, and test whether a model according to hypothesis 2 fits your data better.
Changes are that after this excersize these two hypothesis are still both viable, one could either a) go for the most simple explanation, being variability or b) gather more experimental data to test both hypotheses.
Hope this helps,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD MSD
PO Box 20, 5340 BH Oss, Netherlands
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Dear Jeroen,
Thanks for the insights.
You are absolutely right with the high variability of the data hypothesis - however I do believe that the trend is valid since it repeat itself in several experiments.
In the second hypothesis the low capacity clearance (biliary excretion) saturation can explain the AUC elevation between 5 and 20 mg doses, but the saturation is not expressed in the AUC ratio between 20 and 80 mg (returns to linearity) or masked by additional process. I wonder if saturation of absorption or saturation of binding to plasma proteins can mask saturation of metabolic clearance?
Thanks again
Arik
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The following message was posted to: PharmPK
Dear Arik,
There are all kind of hypothesis you could propose and subsequently test. Such an approach could end up as being rather resource intensive and therefore I would spend some more time on the variability hypothesis.
You appeared to observe changes in both exposure and terminal phase, based on your models per dose. Let me repeat my previous advice, try capturing data from all doses together in one model, with or without dual (saturable+non-saturable) clearance. Other hypotheses may be tested in a similar fashion. I obviously am model-minded, but the result could enable a more targeted approach in further experimentation. There are simply too many hypotheses to test without such support IMHO.
Best regards,
Jeroen
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