Back to the Top
The following message was posted to: PharmPK
Does anyone have any suggestion how to perform a PK/PD modeling using
urinary excretion data (rate of excretion or total urinary excretion)
for a drug that is not detectable in plasma but measurable in urine ?
Best regards
Gianluigi Poli
Chiesi Farmaceutici (Italy)
Back to the Top
The following message was posted to: PharmPK
Poli,
> Does anyone have any suggestion how to perform a PK/PD modeling using
> urinary excretion data (rate of excretion or total urinary excretion)
> for a drug that is not detectable in plasma but measurable in urine ?
>
First of all you need to find a method for modelling that would let you
describe both plasma concentrations and urine excretion rate
observations. Then set up the method for a one compartment disposition
model and bolus and make the renal clearance be the same as the plasma
clearance of your drug.
In the simplest case (bolus input) there are 2 parameters you might
want to estimate: volume of distribution/Ff and clearance/Ffu where Ffu
is the product of the unknown extent of bioavailability and unknown
fraction excreted in the urine. To do the modelling you will have to
assume Ffu=1.
Because you don't have any plasma concentrations you can only estimate
clearance from the time course of urine excretion rate by fitting the
model to the urine excretion rate observations. You will therefore have
to assume a reasonable value for volume. If you have no idea what it is
then fix it to 1 but remember that the estimate of clearance will be
dependent on the value you assume. Because the ratio of
clearance/volume is directly identifiable the relationship between the
true and estimated values is CLtrue = Vtrue*CLest/Vfix.
It is not essential to have plasma concentration data to fit the urine
data with this model.
If your urine excretion rate time course gives some clue about the
absorption rate (i.e. excretion rates rise to a peak and then fall) you
can describe the drug absorption process e.g. if you assume first order
input then you can estimate the absorption rate constant (ka).
You indicate that you want to do PKPD modelling. If you have got drug
effect observations then you can learn more about the time course of
plasma concentrations by simultaneously fitting the time course of
urine excretion rates and effects. The success of this will depend on
how much effect data you have and the complexity of the model needed to
describe any delay between plasma concentration and effect.
Examples of fitting urine excretion rate data with both bolus
[bo1renal] and first order [ka1renal] input can be found here:
http://www.health.auckland.ac.nz/courses/Pharmcol716/
Error%20Models%20and%20Objective%20Functions/olsels.xls
[Sorry about the long URL which you will have to manually re-create if
word-wrap splits it across 2 lines]
The examples use Excel to simulate urine excretion rate data (including
residual error). The parameters of the PK model and the residual error
model can be estimated using the Excel Solver. You may enter your own
real urine excretion data (in the Yobs column) if you want to try it
out on your own data.
An extended least squares (ELS) objective function is minimized by the
Solver. You can change this to ordinary least squares (OLS) or
iteratively re-weighted least squares (IRLS) by changing the Solver
target to minimize.
The residual error model assumes a proportional error for IRLS and ELS.
You can change this by modifying the Virlsi or Velsi formulae which
define the predicted variance of the residual error.
Some background on objective functions and error models can be found
here:
http://www.health.auckland.ac.nz/courses/Pharmcol716/
Commments and suggestions for improvements in this material are very
welcome.
[You can find the Solver under Tools menu. If it's not there then go to
Tools Add-Ins... and check Solver Add-In. If you can't see the Solver
Add-In then you will need to the Office Installation program and ask
for the Solver Add-In to be installed. It comes free with all versions
of Office but unfortunately it is not installed by default. While you
are doing this you may want to install the Analysis ToolPak for simple
statistics.]
Nick
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Back to the Top
The following message was posted to: PharmPK
Look At the Loo-Reigelman Equations (Gibaldi's book on PK
Stanley Cotler
Non-Clinical Drug Safety
Nutley, NJ 07110
Phone 973-235-2857
Fax 973-235-7010
Back to the Top
The following message was posted to: PharmPK
Many thanks for the answer.
Unfortunately I have some problem in using the Excel file you
suggested. Please where may I find some explanations how to use the
model ?
In addition when I perform a fitting of the urinary data, I obtain an
estimate of plasma concentrations; I am asking if these estimated
plasma concentrations (lower than the limit of quantification of the
method) should be used together with dynamic response for PK/PD
modeling ?
Thanking you in advance, best regards
Gianluigi Poli
[It might be better if you keep the drug in the body as amount (in your
model) and not try to use concentrations (even with a volume of 1). You
could then model the PD part in terms of amount. You would still have a
EC(50%) type parameter but as effective amount 50%. Same number of
parameters, except no made-up V term. - db]
Back to the Top
The following message was posted to: PharmPK
Poli,
Poli Gianluigi wrote:
> Unfortunately I have some problem in using the Excel file you
> suggested.
Please describe the problems e.g. cannot open Excel file, don't know
how to enter data, etc.
> Please where may I find some explanations how to use the
> model ?
Look at the Excel formulae. Read the Excel help on the Solver Add-in.
If you put some effort into trying to describe exactly what you think
you need explaining you may find the answer becomes clear to you.
> In addition when I perform a fitting of the urinary data, I obtain an
> estimate of plasma concentrations; I am asking if these estimated
> plasma concentrations (lower than the limit of quantification of the
> method) should be used together with dynamic response for PK/PD
> modeling ?
It makes no difference if the PREDICTED plasma concs are lower than the
quantification limit of the method. The PREDICTED plasma concs are fine
to predict MEASURED urine and MEASURED effect observations. This is one
of the great advantages of using models insted of relying only on
observed data.
Nick
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)