Hi,Back to the Top
I've just obtained my very first Pk data. I'm learning as I go (I have
no formal training in PK analysis as you can probably tell), so any
information will be very helpful. Please feel free to point out any
and all flaws.
I have been dosing nude mice IP with a novel drug at 20 mg/kg qd2-3 X 6
and seeing fairly good anti-tumor efficacy. I want to get some idea of
ways to improve this efficacy by looking at PK parameters.
I've just looked at data from 3experiments in whichdrug wasgiven
aseither a single IV injection of 20 mg/kg (2 exps) or a single IP
injection of 20 mg/kg (1 exp). The drug is formulated in a mixture of
1:1 cremaphor and ethanol and further diluted into 5% dextroseat a
ratio of 1:10. I took samples at 5', 10', 30', 90', 360' and 24hr for
each exp. I actually gave more absolute drug in the IP exp due to
slight differences in average mouse weights for these exps (502
microgram given in IP exp, 440microgram given in IV experiments). I
quantitate drug using an LC/MS using the mass spec for quantitation and
an internal standard that differs from the original drug by addition of
a methyl group. The drug is first purified from plasma using a Waters
Oasis HLB column (approximately 85% recovery of both IS and drug).
I'm very new to using WinNonLin and definitely do not fully understand
all the features; however, I used a noncompartmental model 201
(IV-Bolus Input) to analyze the IV data and a noncompartmental model
200 (extravscular input) to analyze the IP data. I don't know when one
uses a compartmental model to analyze data yet, so these may not be the
I wanted to compare the IV and IP data. I assumed I would have a lower
AUC for the IP than the IV but somehow in comparing the two numbers my
IP AUC is 500% of my IV AUC. The terminal half life (HL_lamda Z I
think?) is 200 minutes for IV and 120 minutes for IP. I get a much
higher peak value with my IP administration although my values are
higher in general for all timepoints from the IP mice.
Even with my limited understanding of PK analysis none of this makes
sense. I'm wondering if there may be some problem with the way in
which samples were obtained or handled or if this is a calculation or
experimental design problem.
Any insight that anyone can provide is greatly appreciated. I did read
in the archives about a similar situation but in that case the IP AUC
was only 150% of the IV. Someone suggested Flip flop kinetics. What
Thanks so much,
by now i think you have come to a close approximation that the halfBack to the Top
life of your antitumor drug is approximately between 2-3 hrs.so i
advice you to have more sampling points between 0 - 4 hrs so that you
can more accurately approach to a much closer value of T-half.also
simultaneously while estimating the concentrations i feel you can get a
much better value of AUC for each of the test groups.i think this will
a bit be helpful for your study.
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