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hi all
I have a question regarding the use of noncompartmental analysis in
winnonlin for multiple oral dose data. My concentrations are not at
steady state (very long half-life of drug) so I cannot make this
assumption, and there is no other option for entering multiple doses
(i.e. it only has the options; dose and time of last dose). my
question is thus, should I enter my initial time of dosing and the
total dose amount for the entire period and run it that way? As far as
I understand it, for the calculations of AUC etc, an nca analysis
makes no assumptions and uses the actual observed concentrations, and
thus the values shouldn't differ for certain parameters whether it
assumes a single dose or multiple. I'm not sure however that this is
what wnl is doing...
thanks
k
[I think AUC calculations will require complete first dose data or one
dose interval data at steady state - and linear disposition?? Modeling
with a compartmental model may give you more information - db]
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The following message was posted to: PharmPK
Hello Katya,
The answer to this question depends upon your endpoints, i.e. what PK
parameters are you trying to calculate?
If, for example, you are looking for elimination rate, single-dose AUC,
and AUCinf, you could perform NCA on just the single-dose profile.
If you are looking for AUC's for the other doses, e.g. to capture
exposure to drug for the additional doses, you would need to profile the
data and do a separate NCA for each dose. One way to do this would be to
add a column to your input dataset, e.g. "DoseNum," and enter in values
that correspond to which dose was administered, e.g. "1" for the first
dose, "2" for the second dose, and so on. Then use this new column as a
sort variable in your NCA model. You would then get a separate AUC
calculation and Cmax for each administered dose.
Another approach would be to use one of WinNonlin's PK models (e.g. PK
model 3), as the PK models support multiple doses.
Sincerely,
Christopher Mehl
Pharsight Software Support
Email: support.-a-.pharsight.com
Web: http://www.pharsight.com/support/support_home.php
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The following message was posted to: PharmPK
Katya-
You can treat multiple dosing not at steady-state as a single dose
with the dose entered into WinNonlin as the sum of all doses.
WinNonlin will compute the AUC but you will have to specify the
timepoints for half-life. AUMC cannot be computed by this method. It
has always been in my experience quite inaccurate. So suggest
reporting volume using Vz rather than Vss. One other thing to look
out for is the sample collection timepoints. If they are spread far
apart you will over estimate segmental AUC in going from point to
point. But if you have frequent sampling (or fast initial
distribution) then it won't be too bad.
This is a problem that lot's of folks in the biotech area have,
expecially for monoclonal antibodies in Phase I studies, where it is
not clinically feasible to do a lot of sampling on patients, half-life
is long and dosing is not to steady-state. Some time ago, I used a
Fortran program that did the AUC calculations for each dose interval
and computed Cmax and Tmax for each interval. This of course assumes
rich sampling across all dose intervals.
The other recourse is to fit a compartmental model across the entire
profile.
Dan Combs
Combs Consulting Service
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The following message was posted to: PharmPK
Dear katya,
You can enter your data for different doses and sort it by day or
number of doses i.e. dose 1, 2 , 3 etc and perform NCA to get PK
parameters at each dose.
This will give you PK parameters such as AUC, Cmax, Tmax etc
However if you are interested in knowing the steady state parameters,
WinNonlin has an option of giving you steady state parameters (click
on the check box steady state). You need to enter time as cummulative
time and then also provide Tau or dosing interval. In the dose you
need to enter the total dose.
The output will give you steady state parameters such as AUC0-tau,
Cmax ss, Cmin ss etc.
Hope it helps
Regards
Tausif Ahmed, Ph.D.
DMPK, Sai Advantium pharma Ltd.,
Pune, India
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