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Dear all,
I have a very unusual situation and wanted to see about getting the
collective opinion on the group regarding the best way to handle this
modeling problem. I have a drug that is given by 30 minute
infusion. Samples were collected at predose, mid-infusion, end of
infusion, and serial thereafter for 8 halflives. In about a third of
the samples the mid-infusion sample had a considerably higher
concentration (25 to 50%) than the end of infusion concentration.
This phenomenon occurred across multiple studies, on multiple days
(although not always in the same subject twice), and across multiple
analytical runs. I have ruled out switched tubes and analytical
error. For a variety of reasons this appears to be a valid phenomenon.
Now, how best to model it or even explain it. The best I have been
able to come up with is it is a distribution phenomenon. In
discussions with another modeler I was informed that he just reviewed
a paper having the same phenomenon and in that paper the authors
discarded the midinfusion data. I have tried using time-dependent
volumes using continuous and change-point functions. I get modest
improvements in goodness of fit compared to completely ignoring the
phenomenon which has a residual variability of about 30% using a 3-C
model.
As a company we have decided to pursue an oral formulation of this
drug so it seems to me that modeling the iv data to the point of
completely capturing the phenomenon may be a modeling exercise and
not of any real value any longer.
Any opinions on the validity of throwing out the data, just running
with the model that ignores the phenomenon and has high residual
variability, or something else I haven't been able to think of would
be appreciated.
Thanks,
pete bonate
Peter L. Bonate, PhD, FCP
Genzyme Corporation
Senior Director, Pharmacokinetics
4545 Horizon Hill Blvd
San Antonio, TX 78229 USA
peter.bonate.at.genzyme.com
[Any pharmacology to the compound that might affect distribution,
blood flow changes etc.? - db]
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We saw this behavior with doxorubicin infused over 20 min to parrots
and it seems to be quite reproducible (Gilbert et al. Aust Vet J
2004; 82:769-772) . We put it down to mid-infusion fluctuations in
serum levels as a result of altered cardiac output from the
concentrated infused drug, based on the papers by Richard Upton (Br J
Anaesth 2004; 92:475-484 ; Intensive Care Med 2001; 27: 276-282).
Cheers BC
Bruce CHARLES, PhD
Associate Professor
School of Pharmacy
The University of Queensland, 4072 Australia
[University Provider Number: 00025B]
B.Charles.-at-.pharmacy.uq.edu.au
http://www.uq.edu.au/pharmacy/brucecharles/charles.html
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Hi Pete
I assume that this compound is NOT a biologic, owing to the plans for
oral formulation, but can you give any information on the general
class of agent that you are dealing with? That can provide some
information on possible causes of this sort of behavior such as what
Bruce suggests below. You could also get extravasation or some local
inflammation that is causing altered PK in the case of anti-
neoplastic agents
Diane
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The following message was posted to: PharmPK
Bonate, Peter wrote:
> Dear all,
> In about a third of the samples the
> mid-infusion sample had a considerably higher concentration (25
to 50%)
> than the end of infusion concentration.
Hello Peter,
What do you know about the effect of your drug on the circulatory
system? The drugs I often work with can change cardiac output with
consequent changes in both steady-state and non-steady state blood
concentrations. I have used recirculatory models to describe this type
of behaviour, but this approach does require some understanding of what
the circulation is doing. Higher mid-infusion concentrations imply a
lower cardiac output - perhaps the drug has a transient vasoconstrictor
effect?
Regards, Richard
--
Dr Richard Upton
Principal Medical Scientist/Senior Lecturer
Discipline of Anesthesia and Intensive Care
Royal Adelaide Hospital/University of Adelaide
North Tce, SA 5000, Australia
richard.upton.at.adelaide.edu.au
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The following message was posted to: PharmPK
Did you monitor renal function during testing?
increases in ERBF and GFR, induced by the drug. Specific clearance of
the drug by a given organ whihc may either be increased or decreased by
drug insult- particularly an increase, could result in the apparent
changes.
Ed O'Connor, PhD
Technical Director, Immunoanalytical
Tandem Laboratories
115 Silvia Street
West Trenton, New Jersey
609-228-0243
ed.oconnor.aaa.tandemlabs.com
[Peter, how close were you to steady state at the end of the
infusion? - db]
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The following message was posted to: PharmPK
Hi Peter,
Is the compound highly protein bound? Did you have organic solvent in
your drug solution? Why I am asking is, if the drug solution contained
any organic solvent which when infused for long periods could gradually
denature the plasma proteins leading to decrease in the fraction of drug
bound. This increases the concentration of free drug and therefore the
clearance of drug from plasma compartment (where drug is often measured)
by means of increased uptake into tissues (in case of liver this could
lead to increased metabolism) and/or increased biliary/urinary
excretion.
In your case, it is possible that the percent bound drug at mid infusion
is higher than at the end of infusion!? You can check if this is the
case by infusing blank formulation and estimating the extent of protein
binding for your drug using the plasma obtained from blood samples
collected at pre, mid and end of infusion.
Hope this helps.
Cheers!
Kasiram.
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The following message was posted to: PharmPK
Dear Peter,
I remember coming across a similar behaviour with a fairly lipophilic
compound (a dihydro-pyridine vasodilator).
The problem was that the compound partly adsorbed onto the inner
surface of the infusion line. Practically speaking, when the infusion
rate (amount vs time) was set to a constant, the infusion rate
actually measured and delivered at the end of the infusion line
varied with time. More specifically, it dropped very quickly, went
through a minimum, then increased slowly to a plateau (less than the
nominal infusion rate). The phenomenon was simply evidenced by a
simulated infusion. Correcting the PK model for the actual input rate
kinetics greatly improved the PK fits.
By chance, did you get into a similar situation?
Hope this helps,
Henri
Henri MERDJAN
Head of Drug Metabolism and Pharmacokinetics
NOVEXEL S.A., Parc Biocitech, 102 Route de Noisy
F-93230 Romainville, France
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