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Hi,
I am trying to predict plasma conc. vs. time curve for a two-
compartment drug but strangely we are achieving 10X higher
concentration that what I predict using WinNonlin based on the PK
parameters obtained from fitting 1mpk IV study: V1=2.23 L/kg,
K10=1.09, K12=2.31 and K21=1.84. The study is a typical rat (IV Bolus
+ infusion) experiment - Bolus dose of 16mpk at time zero + 4mpk
infusion dose for next 2hr. The actual PK curve and it's shape is
exactly same as what I predict based on 1mpk parameters but I am
getting 10X higher concentration at all time points.
Any comments why I am seeing these 10X higher concentrations? I don't
think saturation or non-linearity at the higher doses can explain this
since shape of actual curve is exactly same as what I predicted (i.e.
initial distribution phase, stead state phase and terminal clearance
phase after 2hrs). We are using an emulsion formulation in this new
study vs. a standard vehicle we used for the 1mpk study. We are dosing
highest soluble amount of the drug so it's not possible that we
mistakenly dosed 10X higher doses than what we think. Any Insights?
Thanks in advance for all feedback. Have a good weekend.
--
Pratap Singh
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The following message was posted to: PharmPK
Hello Pratap,
Your starting concentration should be around Dose/Vd. Maybe a better
model for infusion would be to fit your microconstants after a 16 mpk
bolus dose alone with your emulsion formulation, and then do the
fitting? (just in case there are formulation or dose effects). Could
your formulation somehow affect the volume of distribution of the
drug, I wonder? Or is this a very silly thing to say?
I tried out your model for fun with the information you provided to
see if perhaps the model itself was at fault. Does your fit look
anything like this?
Time(h) Concentration(ug/mL)
0 7.174887892
0.2 4.117222113
0.4 2.882399713
0.6 2.347715129
0.8 2.084929953
1 1.930460213
1.2 1.821598176
1.4 1.734103866
1.6 1.658422619
1.8 1.590620843
2 1.528930156
2.2 1.33892924
2.4 1.206187476
2.6 1.100078134
2.8 1.008547122
3 0.926647896
3.2 0.852170361
3.4 0.78397307
3.6 0.72134565
3.8 0.663763962
4 0.61079505
4.2 0.56205931
4.4 0.517214594
4.6 0.475948779
4.8 0.437975689
5 0.403032374
5.2 0.370877016
5.4 0.341287146
5.6 0.314058066
5.8 0.289001421
6 0.265943882
Cheers,
-Dave
--
David Dubins, Ph.D., B.A.Sc.
Global Bioequivalence Consulting
Assistant Professor, Leslie Dan Faculty of Pharmacy
University of Toronto
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Dear Dave,
Thanks for your comments.
You raised an intriguing point - can my formulation affect the volume
of distribution of the drug? To get the 10X higher concentration
(compared to those predicted using 1mpk IV parameters), both Vd and CL
has to be 10 times lower in order to get the same terminal Kel. I am
not sure if how a new formulation can make that happen if that's the
reason.
The concentration you have simulated are consistent with my
predictions as well. Problem is, the actual data are 10X higher at all
the time points though overall shape of the curve is same.
Lastly, I would like to correct a typo I made in my original mail: my
infusion dose is 14mpk and not 4mpk. The duration is same: 2hrs.
- Pratap
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The following message was posted to: PharmPK
Hi Pratap,
The starting concentration *in theory* should just be your bolus Dose/
Vd, regardless of the infusion rate. Are the data in different test
animals? Perhaps the distribution volume varies widely from animal to
animal? If you have the opportunity, I think the thing to do would be
a dose ascending PK study in animals to see if this is an anomaly. Or,
just do the 1 mpk dose with the emulsion formulation this time to see
if you still get 10x higher results. It makes no immediate sense to me
why an IV drug would change distribution volume with dose. I've heard
of a depot effect at the injection site, where the drug sits there,
clinging to the inner lining of the venous wall, it doesn't
immediately distribute. In this case, perhaps the emulsion version of
the product doesn't do this, or the depot effect is overwhelmed
because the dose is so much higher? I have no idea if this could be
happenning for you, just brainstorming. Here is the model recalculated
with a
14 mpk infusion over 2 hrs:
Time (h) Concentration (ug/mL)
0 7.174888
0.2 4.450971
0.4 3.418274
0.6 3.02958
0.8 2.885895
1 2.835213
1.2 2.819646
1.4 2.817159
1.6 2.819382
1.8 2.823146
2 2.827266
2.2 2.364057
2.4 2.084895
2.6 1.884052
2.8 1.720589
3 1.578305
3.2 1.450473
3.4 1.334022
3.6 1.227312
3.8 1.129287
4 1.039149
4.2 0.956226
4.4 0.879929
4.6 0.809723
4.8 0.74512
5 0.685671
5.2 0.630966
5.4 0.580625
5.6 0.534301
5.8 0.491673
6 0.452445
Hope this helps,
-Dave
--
David Dubins, Ph.D., B.A.Sc.
Global Bioequivalence Consulting
Assistant Professor, Leslie Dan Faculty of Pharmacy
University of Toronto
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