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A scientific conundrum on which I am hoping the group can help shed
some light...
I am currently working with a US pharma company who has a highly water
soluble drug in development which has been shown via in vitro studies
to be a significant substrate for 2D6. The client has recently
received TK data from their 28 day repeat dose rat tox study. The
results were as follows:
* Drug exposure was significantly higher in females compared to
male rats on both Day 1 and Day 28. The average male to female AUC
ratio was about 0.65
* Drug exposure increased with increase in dose in both genders.
However, the increase was more than dose-proportional at doses up to
30 mg/kg. For a 1.67-fold increase in dose from 6 mg/kg to 10 mg/kg,
the increase in exposure was circa 4 fold. A further increase of 3-
fold in dose from 10 mg/kg to 30 mg/kg resulted in circa 9- fold
increase in exposure
* The accumulation ratio, calculated as ratio of AUC on Day 28 and
Day 1 was circa six but reduced with dose
* Tmax ranged from 0.5 h to 12 h on Day 1, and the Tmax was
delayed with increase in dose. In addition, the pk profiles are
characterised by a prolonged plateau for about 12 hours post-dose on
both Day 1 and 28.
Two questions :
* Any theories on the marked gender differences between males and
females? I am presuming that the lack of dose proportionality is
related solely to first pass effects, however, I would be happy to
hear an alternative theory.
* I find the prolonged plateau in the pk profile surprising; what
can we expect in humans in terms of single dose and multiple doses?
All theories welcome.
Please feel free to email directly (ian.aaa.ianwildingassociates.com ) if
appropriate.
Best regards
Ian
Ian Wilding Associates Limited
10 Glebe Street
Beeston
Nottingham
NG9 1BZ
UK
Email : ian.at.ianwildingassociates.com
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The following message was posted to: PharmPK
Saturation of an elimination pathway could account for all of your
findings.
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The following message was posted to: PharmPK
Hi Ian,
It is quite frequent to see a male versus female diffence in the rat
exposure as the 2 genders do have a quite dramatic difference in liver
enzyme "equipment".
We would need further info with regards to the relative increase in Cmax
as a function of dose as compared to the auc,
I do agree that it seems that saturation could be a reason
The decrease in Rac could be either variability. We would need to know
how much is the 2decrease in Rac" as a function of dose.
With regards to comparison to man you need to look at the in vitro data
available to predict a similar outcome, but it is often unlikely as (1)
the range of dose if far less extensive and (2) saturation depends also
on the liver enzyme affinity which could be very different in man.
P.
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