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I have a compound that shows time-invariant kinetics after repeated
dosing from a solid dosing formulation but is clearly time-dependent
when administered from an oily liquid formulation. Cmax is
approximately double that expected, so I'm assuming there is a
formulation-related difference in the rate of bioavailability? It's
complicated by the fact that the extent of metabolism of the compound
to its major metabolite is less from the medium-chain triglyceride
(MCT) formulation (I thought this might be preferential uptake by the
lymph thus avoiding first-pass metabolism, but MCT formulations do not
appear to undergo extensive lymphatic absorption).
Is anyone aware of other examples for such behaviour or could throw
some light on these observations?
Best Regards,
Charlie Brindley
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Hi Charlie,
It seems like you're getting slower absorption when you use the solid
dosing formulation. The dissolution rate could be the rate-limiting
step in absorption. When you use the oil formulation, absorption is
faster, leading to the higher Cmax. Do you also see a shorter Tmax and
higher AUC? The difference that you've seen in kinetics and metabolism
could easily be explained by the saturation of metabolism when the
absorption is fast (not limited by solubility). This would lead to more
parent being absorbed and less first-pass metabolism. It could also
explain the accumulation if you see a difference in T1/2 / MRT for the
two formulations.
I hope this helps.
Beverly Knight
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Hi Beverley,
Many thanks for your response. I agree that a faster rate of absorption
could result in reduced first-pass metabolism and greater
bioavailability of
parent compound. AUC of parent was greater from the liquid formulation;
however, tmax does not appear to be shorter compared to the solid form.
Furthermore, absorption-rate limited kinetics would not explain the
time-dependent kinetics from the oily formulation. There is no
appreciable
difference in terminal half-life of parent compound from liquid
compared to
solid formulation (multi-phasic disposition). Flip-flop kinetics seems
improbable because the elimination half-life is in the order of 2 days.
I successfully fitted a linear PK model simultaneously to the parent
and
metabolite concentrations measured on days 1, 7, 14 , 21 and 28 from the
solid-dose form (the fit was very good). However, the same model would
not
adequately fit the repeat-dose parent/metabolite data from each of 20
subjects using the liquid formulation.
A precedent for apparent, formulation-related non-stationarity would
be very
interesting...
Charlie
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Would the oil stimulate realease of bile???
Edward F. O'Connor, PhD
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The oily formulation may trigger bile release and increase rate of
absorption. However, this mechanism doesn't explain the time-dependent
kinetics?
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Charlie,
Can you be more specific about the time-dependence? Are there changes
in AUC
as well as Cmax (and presumably Tmax)?
Is this a 3A4 substrate? A transporter substrate?
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Hi Walt,
The extent of accumulation in plasma of Cmax from the MCT formulation is
greater than that from the solid-dose formulation. By contrast, the
extent
of accumulation of AUC is similar. There is no apparent difference in
tmax
between the two formulations.
CYP profiling studies have not been performed but it is metabolised in
liver
preparations. However, it doesn't appear to inhibit or induce CYPs in
rats.
There is no information on transportation.
Thanks for any suggestions.
Charlie
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Charlie
Would your conundrum be solved by a saturable recycling phenomenon? If
the MCT formulation presents more compound to recycling than it can
reabsorb then some of the dose must be lost by passing on down the gut
while a slower presentation from the solid dose form could catch up
AUC-wise. This thought was triggered by the earlier question of
whether bile might be involved because the amount of bile produced
would be limited, especially in fasting volunteers of course.
That would allow for your higher Cmax but the same tmax which would be
due to the primary absorption. That would be more likely if the
primary absorption site was a relatively limited section of gut.
Andrew
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Hi Andrew,
The most likely mechanism for higher Cmax from the MCT formulation is
capacity-limited first-pass metabolism due to a faster absorption rate
compared to the solid-dose form.
However, I can't explain the apparent time-dependent kinetics using
the MCT
form observed in healthy subjects at two dose levels and also in
patients
(but not apparent using the solid-dose form). The time-dependency is
manifested as higher than expected Cmax on day 28 after repeated once or
thrice-daily dosing compared to the first dose. I can't see how
saturable
recycling would account for this observation. By the way, the subjects
were
not fasted.
This forum is probably not suited to discuss the time-dependency and the
detailed comparative kinetics of this compound. I was hoping that
someone
would know of a precedent for formulation-related, time-dependent
kinetics.
Regards,
Charlie
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