Back to the Top
Dear all,
I have a small problem and a couple of remedies I would like to share
with you. A compound was administered iv bolus dose (left arm, 10
seconds injection time) and plasma samples were collected (right arm)
at the following time-points: pre-dose, 1, 2, 3, 4, 5, 10, 15, 30, 45
minutes and then hourly up to 12 hrs. Not surprisingly, the maximum
observed concentration is not the 1 minute sample but rather 2 (or in a
couple of subjects 3) minute sample. This is obviously due to the time
it takes for the compound to distribute within the plasma compartment.
The question is how deal with this from a modeling point of view. One
way would be to write the model as an infusion, another to ignore the
first time-point and use data from the highest concentration (Cmax) and
onward. I have tried both approaches and they give very similar
parameter estimates.
What are your opinions? Please feel free to comment on any of the two
approaches and also provide alternative ones.
Best regards,
Toufigh Gordi
Back to the Top
Dear Toufigh,
Looking at your study design, I would be interested in knowing the
scope(objective) of the study as your information in mail doesnt provide
the same.
If you are in quest of general pharmacokinetic parameters, how does it
really matter if you are sampling at 5 minutes followed by 5 minutes
intervals in early phase which would provide enough information.
In regard to the options provided by you, if we consider the data points
from 1 to 45 minutes, 10 seconds dosing time will definately make an
impact at 2 or 3 minute sampling points but impact on the general
profile (Up to 12 hrs) would be rather negligible. Thats how both
designs
are giving same values for PK parameters.
Although, both approaches are giving same results, infusion model would
give more precise information but this model may not be suitable for
such
studies.
If your study intention is to distinguish the PK parameters at early
points, NON MEM would be better option.
I hope this information will be helpful to you and I would be more
interested in knowing the objective of such study.
Have a nice day!
Prashant
Kole Prashant, M.Pharm (Ph.D)
Faculty,
Pharmacy Group,
Birla Institute of Technology and Science, Pilani
Rajasthan, 333031
Phone: (O) 01596-245074-Ext-458
(R) 01596-242824
Fax: 01596-244183
Alt.Email: prashantkole.aaa.rediffmail.com,plkole.at.yahoo.com
Back to the Top
Toufigh, this is a very nice study. I have often disputes because when
i am teaching and tell people the concentrations during the first
minutes in the opposite arm is actually less than Cmax, they not often
believe that. i have studies were in some volunteers it takes more than
5 minutes, even with a 20 minute infusion time! (not average weight
though).
it depends what you want the model to represent and what you want to
conclude from it. Even the Cmax in the opposite arm may not be the Cmax
in all parts of the body at that timepoint, although it is a reasonable
approach. In the (i assume twocompartment open) model we do assume an
even distribution (by assuming one concentration at a certain
timepoint) , and then estimate the parameters from the data. From that
point of view, the parameters estimated for distribution (k12, k21,
t1/2a depending on your model description) should thus be determined
from the Cmax after even distribution within plasma and the first
timepoints be discarded otherwise the parameter estimates not only take
the distribution to tissues into account but also distribution within
plasma and thus be a composite.
it will depend on the values of k12 an k21 whether there will be
significant differences between in and excluding them - from your
fitting results apparently the influence is marginal.
an alternative would be to extend the model of course, and indeed use
an infusion time. the question then is whether to use a zero order or
first order infusion - because, again, the distribution within plasma
has to be taken into account here as well. this becomes very
complicated and more philosophical (but needs to be realized!!) and
surpasses the purpose of the exercise
johan mouton
Johan W Mouton, MD PhD
Dept Medical Microbiology and Infectious Diseases
Canisius Wilhelmina Hospital C-70
Weg door Jonkerbos 100
6532 sz Nijmegen
The Netherlands
tel + 31 24 3657514
fax + 31 24 3657516
email mouton.aaa.cwz.nl
Back to the Top
Hi!
The study was obviously not designed by a pharmacokineticist. A PK
person would know better NOT to sample so early and create problems
:-).
This was a simple dose-escalating study, investigating the PK of the
compound. As I said, the study was designed by someone with little PK
background. A 3-comp model fitted the data very well, with very rapid
initial distribution phase (half-life of 3 minutes, followed by
somewhat slower decline and then a third phase. The elimination
half-life of the compound is roughly 2 hours.
Toufigh
[A standard three compartment model after IV assumes rapid mixing. If
the early data 'violates' that assumption the data should be discarded
;-) at least for the modeling or you could develop a more complex model
(e.g. see Richard Upton's earlier post about recirculatory pk) to
include the interesting early data - db]
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)