Back to the Top
I do not work in the Drug Industry field and I need some guidance in
designing an initial PK study in rats. I was hoping someone could
suggest a reference (or comments) as to guidelines in performing
initial PK studies in rats on a lead compound. I am going to analyze
the compound by HPLC-UV from plasma and possibly brain tissues. Is a
single dose study sufficient to calculate PK parameters? Assuming the
HPLC assay is very sensitive, is there a minimum number of time points
to analyze?
Back to the Top
The following message was posted to: PharmPK
Single dose is good initially. Any approach is obviously compound
and dose dependent, though so start with a very low dose that you can
calculate based on blood volume.
Very sensitive is very relative.
What is the actual LLOQ for your method? This will elicit a few
comments but at this moment in time it is the lowest concentration you
can report with accepted and acceptable reliability. This will also
define indirectly the longest time point for sampling.
You can get an idea of the profile using Simulations Plus or other in
silico software (ACD ADMET) initially. Then you would put those
results to the test in actual animals.
You want to get enough points to define the distribution and
elimination phases. You might get an idea from the in silico work or
you could do a search on compounds similar to the one you are using.
Then apply that. You may need to adjust timepoints to capture the
profile.
Back to the Top
Alan
If i were you and if the drug has never been evaluated in animal
testing, i would first dose a few animals (2-3) to observe where the
drug peaks (if given extravascularly) and how much could be captured
based on the assay you have. Rats being small animals you may have a
limitation to the number of blood samples depending upon the dose you
are going to administer and also by the route of administration. 6-8
blood samples may suffice initially but once you have the preliminary
data you could improvise in many ways. I am not sure what route you
plan to administer and how much you intend to give each animal. Also
it is not clear if you are going to cannulate (to get a complete
profile from an animal) or you ae going to sample from the tail or via
intracardiac sampling (where the number of samples may depend on the
volume of plasma you need to analyze for each point). There is a
publication by Brian Davies (attached file - not attached - db) that
may help you decide the volume that you could withdraw per time point
per animal.
Good Luck
Manish Issar, Ph.D
[Brain Davies and Tim Morris, Pharm. Res., 10(7), 1993, pp 1093-1095
Back to the Top
The following message was posted to: PharmPK
Dear Alan,
In general, you want to ask and answer the question "what are my study
objectives". Making a list of well-defined "things you need to know"
helps
in systematically working your way to those objectives.
For example, you may want the kitchen sink... i.e., separating
bioavailability from Vd, protein binding, toxicokinetics, BBB
clearance, and
metabolite ID/kinetics, or you might just need the terminal half life.
Also, it takes at least three doses to know if you are in a linear
range of
kinetic processes. If you are (or not), this may influence your
approach to
extract PK parameters. For example, noncompartmental parameters are
arguably meaningless for drugs with nonlinear processes, despite
numerous
papers on parameterizing dose dependencies.
The number of sample points? The simple answer is that it depends on
the
drug half-life, but its actually a fairly provocative topic that won't
be
properly addressed here. Often sample points add virtually no usable
information or are "just not in the important places". There are
simulation
techniques that assist with study design (Both Bonate and Gabrielsson
have
very good texts that discuss these topics). If you know little about the
compound behavior, it may be easiest to use one test group to sample as
often and as long as reasonable. Then you will know. Not to mention,
you
can only stay up but so long.
Good luck
-Shawn
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Dyson Bldg., Rm 227
Tallahassee, FL 32307
Back to the Top
The following message was posted to: PharmPK
Hi Alan,
If you have no previous in vivo data on your drug, you may start with
increasing single doses in different groups of rats. These groups do
not need to be large. However, the more dose levels you investigate,
the more PK information, and tox or efficacy for that matter, you will
have on your compound. A rational way would be do gather information
from a few dose levels, construct a PK model based on the data, then
use the model to simulate what would happen upon repeated dosing.
Next, do a couple of repeated dosing studies in animals and see if the
observations match what you expected. If they do, you have a good
model and can use if in future studies. If not, you need to find out
the issues, and learn from the new (repeated dosing) data.
The first couple of dosing groups should lead you on how many samples
and when you need to collect in future studies.
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.-a-.tgordi.com
Back to the Top
The following message was posted to: PharmPK
Dear Mr.Alan Myers,
I hope the following link will give you some idea about guidelines on
animal PK studies.
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-7/a/7ae3a.pdf
Regards,
Dr.S.Gunasakaran
Medical Affairs
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 "Initial PK studies in rats" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)