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The following message was posted to: PharmPK
Can anyone suggest how can dose-adjusted AUC values for an NCE increase
with increasing iv-bolus doses, but the dose-adjusted Cmax values
decrease with the same increase in iv-dose?
Interestingly, there is an increase in both dose-adjusted Cmax, as well
as, dose-adjusted AUC values for increasing oral doses of this NCE.
Any suggestions are greatly appreciated.
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The following message was posted to: PharmPK
Dear Natalie,
I start with the second observation, i.e. a decrase in Cmax/Dose after
increasing iv doses. If you have an instantanous dispostion of the
compound in the central compartment (which I assume is the sampling
site (plasma) in that case Cmax is achieved very early), such a
decrease would mean an increase in volume of distribution with dose.
That could simply be due to saturated plasma protein binding:
Vd = Vp + VT*(fup/fuT)
Vd= volume of distribution
Vp= volume of plasma
VT= volume of "tissues"
fup= fraction unbound in plasma
fuT= fraction unbound in tissue
With increasing dose you might get to a point where protein sites are
saturated and the excess of the drug will be present as free (not bound
to plasma). This results in higher volume and lower Cmax, since Cmax
after an iv dose would be equal to Dose/Vd.
Now, to your first question, i.e. an increase in AUC/dose with dose.
This is indicative of yet another saturable mechanism, this time a
process in the elimination of the compound. If the drug is metabolized,
then it is quite possible that higher doses lead to saturation of the
enzymes responsible for its metabolism. If the drug is excreted through
an active secretion (into urine or bile), that process might become
saturated. Both will lead to an increase in AUC/Dose.
You don't mention what oral doses you give (in comparison to the iv
doses) and what the bioavailability of the compound after such
administration is. However, a low bioavailability might result in lower
plasma concentration of the drug, which clearly do not reach high
enough levels to saturate the system.
Do you know if your drug has a high or low extraction ratio? Feel free
to contact me directly if you have more questions.
Regards,
Toufigh Gordi, PhD
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The following message was posted to: PharmPK
Dear Natalie Graham,
Is the doses given in both the oral route and the IV route is same
or is it different?
Is the vehicle used in both the routes are same or is it
different?
Assuming your NCE shows less bioavailability, then in case of oral
route there is no saturation process as it can be seen in IV route
where 100% of your NCE is in the central compartment(chances of
saturation with plasma proteins is high (reason for decrease in
cmax with increase in doses), chances of saturation with metabolic
enzymes are high and also the elimination process will be affected
(reason for increase in AUC with increase in doses).
If your NCE shows 100% bioavailability then it is very difficult
to answer the observed phenomena.
Regards,
B.L.Suresh
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