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The following message was posted to: PharmPK
Dear readers,
We had studied the pk of a novel chemical entity in a rat model, by
administering bolus iv and oral doses of the compound at 0.1, 0.13
and 0.15 mmol/Kg. Increasing the oral doses lead to a greater than
proportional increase in AUC's,; the same increase in the dose lead
to a less than proportional increase in AUC's following iv
administration of the dose and even a slight decrease in AUC at 0.15
mmol/Kg compared to 0.13 mmol/Kg.
In iv-dosed animals, the clearance remained almost the same in all
doses, the half-life was slightly increased at the higher dose.
In oral cases, the half-life was decreased with increasing dose.
Can any saturation mechanism account for these ambivalent results?
Another observation was that the Cmax values following iv
administration in general accounted for only a small fraction (10 to
20%) of the administered dose. Has anyone any experience with this
situation?
I would greatly appreciate any suggestions or explanations.
Thank you.
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[Two replies - db]
From: David Jaworowicz
Date: Wed, 12 Dec 2001 14:52:45 -0500
To: david.-a-.boomer.org
Subject: Re: PharmPK
Sounds like a classic case of saturation of a first-pass elimination
pathway for your oral administration (either hepatic and/or GI
elimination). Is it known how your drug is eliminated? Saturation of
capacity-limited enzymes will definitely show a disproportionate
increase in AUC with increased dose.
As for Cmax for the IV dose - are you actually referring to the drug
concentration at your earliest sampling time point? Technically, Cmax
is obtained for oral doses (due to an absorptive phase) and an initial
concentration (Co) is obtained for IV doses by back-extrapolating to the
Y-axis for a one-compartment model. Having only 10-20% of your IV dose
as Co or at first sampling is rather small. When is your first sample
being taken post-IV? I suggest no more than a few minutes (preferrably
30 sec. to 1 minute). A very rapid distribution phase can account for a
sharp decline in plasma concentrations immediately following dosing
also. Does your preliminary data show evidence that the drug behaves
according to a two-compartment model? A combination of extensive
distribution and poor sampling time can result in a low measured
concentration.
Another possible question is whether or not your IV formulation is
stable? Is your drug precipitating out before you even administer it,
or precipitating upon administration (which of course would not bode
well with the animals)? If you're not dosing the amount you thought you
were - this could easily explain why your IV dose is following linear
kinetics - there's simply not enough drug to cause any saturation.
Sincerely,
Dave Jaworowicz
---
From: "Rajeev Menon"
Date: Wed, 12 Dec 2001 15:38:53 -0500
To: david.-a-.boomer.org
Subject: Re: PharmPK Nonlinear kinetics
You mention that Clearance does not increase with dose but AUC remains
the same. How is this possible?
Clearance = Dose/AUC, hence as dose increases, and AUC remains the same,
clearance should increase
One of the ways the increase in AUC seen only after oral admin could be
explained as :
Assumption : Highly protein bound and highly cleared drug
Metabolized in the gut wall
After IV administration at higher doses, you are probably saturating
binding. This could lead to increase in free concentration in the plasma
and hence increase in metabolism leading to decrease in AUC (or no
increase in AUC).
After oral administration the drug is being metabolized in the gut wall.
As you increase the dose you are probably saturating this process and
consequently increasing the AUC. The amount of drug in plasma is
probably below the limit where you see saturable protein binding.
This is of course very speculative but you might want to look in to
these processes.
Rajeev
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Thinking further about panteha khalili's comments and question below:
"...In iv-dosed animals, the clearance remained almost the same in all
doses, the half-life was slightly increased at the higher dose.
In oral cases, the half-life was decreased with increasing dose.
Can any saturation mechanism account for these ambivalent results?"
Focusing on the oral dosing part:
Can't these particular observations be due to saturable tissue
binding as well as (or instead of) saturable plasma protein binding?
At higher doses there is a shorter half-life due to saturation of
tissue binding sites. In light of the fact that: (1.) Tissue binding
has no effect on the Clearance of drug (and it was observed that
clearance did not change with dose) and (2.) Half-life is a function
of Volume of distribution and clearance (t1/2 = .693*V/CL):
Higher doses would result in saturation of tissue binding and a
corresponding decrease in apparent volume of distribution and, hence,
a decreased half-life. Then, half-life would be longer at lower
doses as a result of a larger apparent volume of distribution
(because concentrations would be below the saturation level for
tissue binding).
Comments please?
Sincerely,
Dave Jaworowicz
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The following message was posted to: PharmPK
Hi David,
I think you are quite right, I looked at volume of distribution data
and they decrease quite a bit as I increase the dose from 0.1 to 0.13
mmol/Kg and then decrease slightly further as I increase the dose
from 0.13 to 0.15 mmol/Kg. I think you have pointed at a very likely
explanation here.
Thank you.
Panteha
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