Back to the Top
The following message was posted to: PharmPK
Dear All
I have a query regarding the data analysis of a toxicokinetic study
in Rats.
We have administered a single dose of 250mg/kg of a compound
subcutaneously. Time points range from 0-48hrs (12 time points in
total). Although I analysed the data using WinNonLin 5.2 using NCA,
the half life was 6.5 hours despite the fact there were adequate
amounts of the compound at 48 hours. Is this correct? The regression
analysis to determine Lamda was based on 3 times points.
Admittedly the curve appeared to be bi-phasing with an initial peak
at 1 hr, then plateau for 5 hrs then a slow rise to peak at 15 hours
(the Cmax being 5X greater than at 1hr with a gradual decline to 48
hours suggesting 2 compartments, however when analysis was done with
2 compartment model, the software could not fit a 2 compartment
model. The error messages were:
" Error occured during curve stripping"
"Initial estimates cannot be determined with his model".
Is it a 2 compartment model and why is the half life so small?
YOUR COMMENTS WILL BE MUCH APPRECIATED!!!
John.
Back to the Top
The following message was posted to: PharmPK
1) were all three time points above LLOQ ?
2) how good was the fit for the last three?
Ed O'Connor, PhD
Technical Director, Immunoanalytical
Tandem Laboratories
115 Silvia Street
West Trenton, New Jersey
609-228-0243
ed.oconnor.-a-.tandemlabs.com
Back to the Top
[Messages will probably be delayed for the next few days, should be
back in business on Wednesday - db]
John,
There could be several reasons for your observations and since I
haven't seen the concentration-time data, my comments here will be
speculative.
A simple 2-compartment model (IV) will miss the absorption phase
after your SC dosing. Even if you use another model than IV, there is
still a large risk that it won't work since the absorption of
proteins after SC could be very complex and often include different
pathways (Ramakrishnan et al. J Pharmacol Exp Ther. 2003 Jul;306(1):
324-31).
Furthermore, proteins often exhibit nonlinear kinetics and hence the
half-life you estimate based on 3 last concentrations might not be
correct. There are several models of capturing the nonlinearity, e.g.
a target-mediated disposition or a simpler Michaelis-Menten. However,
I would be rather cautious in interpreting model estimates of a
nonlinear system after a single dose.
Last, the line that fits the last three points might not be fitting
the whole time-frame, when you observe concentration decline. This
might again be due to the nonlinear behavior of your compound.
T. Gordi
Back to the Top
The following message was posted to: PharmPK
Toufigh
Thanks for the feed-back and much appreciated. I'm not really familiar
with non-linear PK's.
What sort of modelling do you suggest I use when using Pharsight
WinNonLin version 5.2 software?
John.
Back to the Top
The following message was posted to: PharmPK
John,
I am afraid I have only used WinNonlin for much simpler tasks, i.e.
non-compartmental analysis. When modeling I use NONMEM. However, it
certainly doesn't mean that one cannot implement complex models in
WinNonlin.
If your compound indeed exhibits nonlinear pharmacokinetics, you could
model it by applying a target-mediated disposition (Mager & Jusko: J
Pharmacokinet Pharmacodyn. 2001 Dec;28(6):507-32. ) or a general
Michaelis-Menten system, where (in its simplest form) you replace the
clearance of the drug with two parameters, Vm and km. There are numerous
papers on this and a simple PubMed search would result in hundreds of
references. If there are peculiarities in the absorption process, you
may look at the article I mentioned before (Ramakrishnan et al. J
Pharmacol Exp Ther. 2003 Jul;306(1):324-31).
Again, if your compound exhibits a nonlinear PK, I would be very
cautious making conclusions based on data from a single dose level. One
usually needs good data covering a wide range of doses/concentrations
for a reliable estimation of the model parameters.
Feel free to contact me directly (tgordi.aaa.yahoo.com) if you need more
help.
Toufigh
Back to the Top
Dear all,
Any one have experience in the species difference pharmacokinetics of
peptide drugs.
Have any one found the differerence in PK when it was not mediated by
transporters for peptide drugs.
I will appreciate your reference in this regards.
Thanking you
Yours sincerely
Subramanian
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "PK analysis of a protein compound" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)