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Oral gavage dosing (as suspension in 0.5% aq CMC) at 250, 500 and
1000mg/kg gives the same plasma AUC for each dose level indicating
saturation of absorption. After 6 days dosing plasma AUC is approx
30x lower than measured on day 1 for all three dose levels, there is
no change in the shape of the curve so the rate of elimination appears
to remain constant. A second compound in this series has shown the
same effect.
The compound is neutral with a logP = 5, no evidence of PGP
involvement (in vitro), and moderate in vitro metabolic clearance
(P450 and GSH). With single (oral gavage) doses of 25, 75 and 250mg/
kg exposure increases with dose, but there is no repeat dose data
available at these dose levels.
Should I conclude that repeat dosing is interfering (ie reducing it by
30x) with the absorption of the compound since there is no evidence of
increased clearance, and is there any precedence for this?
Cheers
Alex
[I can see the same AUC for higher dose level after a single dose as a
suspension. The drug in solution, concentration, is the same in each
case and if there is a GI tract 'window' for absorption only the
amount in solution during transit past the window might be absorbed.
No help on the 30x less AUC on repeated dosin though - db]
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The following message was posted to: PharmPK
Alex,
Since the AUC after repeated oral dosing decreases while the elimination
half-life seems to be unaffected, it seems that the CL/F but not CL is
increasing. My guess is that your compound is a high extraction drug (in
a well-stirred model). If the compound induces its own metabolism, it
results in an increased hepatic extraction ratio and therefore decreased
bioavailability, while the systemic clearance, and thereby t1/2, are
unaffected. I worked on a compound with similar properties (artemisinin)
and you might want to take a look at one of our papers, where we
developed a PK model for the phenomenon: Gordi et al., British Journal
of Clinical Pharmacology, 2005; 59:189-98. However, I must admit that a
decrease of 30x is quite significant.
Another possibility is that other transporters are involved and they get
inhibited upon repeated dosing.
Do you have any iv data, especially after repeated dosing, available?
Furthermore, do you have any data on other days than the first and last
(6th) day of administrations?
Toufigh Gordi
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Hi Alex, when were the formulation made for the repeat dosing. Were
they made on the same day or were prepared fresh everyday. If made on
only one day then do you have stability information about the
compound? What about the solubility of the compound. The nonlinearity
could be due to a solubility issue at least with dose escalation. But
I would for sure check the stability/homogenity of the formulation
first.
Thanks.
Neil
Indranil Bhattacharya
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