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Is it possible to find some references for analysis of TK data, when
clearance value increases with dose from 10, 30 and 100 mpk doses in
dog? The clearance for oral 10 mpk dose was 25 mL/min/kg compared to
30 mg dose it is 45 mL/min/kg. The liver blood flow in dog is
considered to 50 mL/min/kg. How is the dose proportionality
considered? What PK parameter should change or not change? If
certain PK parameters are different then what conclusions can be
made? How to interpret data based on changes in PK parameters across
Thank you in advance.
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I am assuming that by PK analysis you are referring to a non-
compartmental analysis (NCA). A couple of questions that come to my
mind, reading your note.
- You mention that CL, or rather CL/F since this was an oral dose,
increases from 25 mL/min/kg at the 10 mg/kg dose to 45 mL/min/kg at
the 30 mg/kg dose. What is the CL at the 100 mg/kg dose? Since in the
NCA the CL is estimated as dose/AUC, it seems that your AUC is no
increasing proportionally with dose. This could be due to lower
amounts of drug being absorbed at higher doses, e.g. because of
solubility issues or some saturable transport system. It could also
be a change in the elimination of the drug. Does the elimination half-
life of the compound changes across doses?
- Have you considered a compartmental (modeling) approach? It might
sound more complex than the simple NCA but is much more powerful in
describing your data. On the condition that you have sufficient data,
you can, e.g., factor in the nonlinear absorption of the drug. It
will also allow you to simulate various situations, e.g. how would
the concentrations look like after a repeated dosing of 50 mg/kg.
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