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Greetings,
I'm working on an NCE where dogs have a dose and time dependent
decrease in CL/F and Rats show only a time dependent decrease in Cl/
F. Half-Lives are long upto 2 weeks and steady state does not appear
to have been reach after 6 month of oral dosing. No sex differences,
all numbers are tight.
Is this a common phenomena with other drugs? Can you give some
examples?
What is the potential relevance (to humans)?
Any interpretation suggestions?
Dog Dose
(mg/kg) Mean Cl/F (L/hr/kg)
Day 15 Day 29 Day
91 Day 181
0.5 3.97 3.67
2.47 2.27
1 2.4 2.74 1.75 1.49
3 1.29 1.24 0.918
0.79
Rat Dose
(mg/kg) Mean Cl/F (L/hr/kg)
Day 15 Day 29 Day
91 Day 181
1 3.071 2.574
1.581 0.963
3 2.924 2.871
1.461 1.125
10 2.798 2.543
1.691 1.461
I would be grateful for suggestions.
Josef Strasser
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The following message was posted to: PharmPK
Hi Josef,
Assuming your estimates of AUCs are correct, one of the possibilities
for what you observe with regard to time-dependent decrease in apparent
clearance might be accumulation of the compound after repeated dosing,
reaching high enough concentrations to saturate its elimination. My
guess is that if you administer a large enough single dose, your plasma
concentrations will exhibit a "typical" non-linear curve, where you will
observe slow decline for a while, changing to a faster elimination rate
once drug concentrations are below your Km. Do you know what enzymes are
involved in the metabolism of the drug?
In my humble opinion, the best way to describe the concentration-time
curve of your compound would be to try a modeling approach, where you
can try to estimate parameters such as Vmax and Km for your clearance.
Toufigh
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The following message was posted to: PharmPK
Joe
It appears that your NCE has different CL mechanisms in the rat and
dog. In
the rat, the NCE is inhibiting its major CL pathway. This could be
due to
inhibition of a CYP450 enzyme which is the major CL pathway for the
drug.
These inhibitions are time dependant and will be seen in such long term
studies
In the dog there are two CL pathways each contributing equally (or in a
significant proportion to each other) where the first pathway is being
inhibited as in the rat resulting in the time dependant reduction
that you
estimate. The second pathway is getting saturated as a function of
dose and
as long as the blood levels are above a certain EC50 value (and
approaching
Vmax) for that CL pathway (assuming that a Michaelis Menten kinetic
model
explains the data), the CL will decrease.
I have not encountered this in practice but have seen different and more
than one CL mechanisms when comparing PK in rodents to that in dogs or
Non-Human primates. In cases where there are different CL mechanisms and
single vs. multiple pathways for CL between species, the potential
for this
finding exists.
As far as the relevance to humans is concerned, I would be concerned
about
the inhibition of a CL pathway. More importantly, is the enzyme
system (??)
that is being inhibited, able to regenerate when the stimulus is
removed. In
other words is the enzyme (??) inhibition reversible and how long
does this
take. What would be the impact of such an inhibition on the CL of any
concomitantly administered drug. This does not minimize the
importance of
the non-linearity due to dose (in the dog) and that may lead to other
safety
issues, however once the drug falls below EC50 the non-linearity goes
away
and hence its impact can be of a minor consequence.
Hope this helps
Anup Zutshi Ph.D.
Pharmacokinetics, Dynamics and Metabolism
Pfizer Inc. St.Louis Laboratories
Mail Stop T-318E
700 Chesterfield Parkway West
Chesterfield, MO 63017
(314)-274-8349 (Tel)
Anup.Zutshi.-a-.Pfizer.com
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