From: "Bonate, Peter" Peter.Bonate@genzyme.com
Subject: [NMusers] Interpreting IOV
Date: Thu, 15 Sep 2005 08:36:41 -0400
Hi, everyone.
I am having trouble intepreting something and I was hoping the group would
help. I am modeling an IV drug given on multiple occasions. The drug is
consistent with a 2-compartment model. When I added IOV to all the model
parameters, the only ones that are "significant" are the IOV terms
associated with V1 and V2, both more than 30%. Now I can understand how CL
can vary from occasion to occasion, but I have a hard time understanding how
V1 and V2 can vary from occasion to occasion. I would also have a hard time
interpreting IOV on Q, but that was not the case here. So my question is,
can someone provide me with a reasonable rationale for why volume terms or
intercompartmental clearance would change from day to day because right now
I am convinced this is modeling nonsense.
Thanks,
Pete bonate
Peter L. Bonate, PhD, FCP
Director, Pharmacokinetics
Genzyme Corporation
4545 Horizon Hill Blvd
San Antonio, TX 78229
phone: 210-949-8662
fax: 210-949-8219
email: peter.bonate@genzyme.com
Interpreting IOV
From: "Perez Ruixo, Juan Jose [PRDBE]" JPEREZRU@PRDBE.jnj.com
Subject: RE: [NMusers] Interpreting IOV
Date: Thu, 15 Sep 2005 15:34:54 +0200
Hi Pete,
Perhaps it could be due to the changes in the hydratation status of the
subjects. It's frequently observed in ICU patients receiving IV fluids. Hope
it helps.
Regards,
Juan Jose Perez Ruixo, PhD.
Principal Scientist. Advanced PK/PD Modelling & Simulation,
Global Clinical Pharmacokinetic and Clinical Pharmacology,
Johnson & Johnson Pharmaceutical Research & Development,
a Division of Janssen Pharmaceutica, NV.
* Turnhoutseweg 30, B-2340 Beerse, Belgium.
* + 32 (0) 14.60.75.08
* + 32 (0) 14.60.58.34
* + 32 (0) 473.91.09.82
* jperezru@prdbe.jnj.com
From: j.bulitta@web.de
Subject: Re: [NMusers] Interpreting IOV
Date: Fri, 16 Sep 2005 02:27:16 +0200
Dear Dr Bonate,
in case you have a rather short (<15 min) duration of infusion and "frequent" samples
within 5-20 min after end of the infusion, you may observe IOV in V1 which may be
influenced by the distribution of arterial and venous blood. I saw a few datasets
when the peak concentration was actually 5-15 min after end of the iv infusion instead
of at the end of infusion for about 30% (depending on the drug) of the subjects.
I did not have replicated doses for those datasets and could not include IOV. However,
dosing the zero order input into a mixing compartment ("gut") and not into the central
compartment improved the objective function typically by >50 points for those
datasets with frequent blood sampling.
Best regards
Juergen
-------------------------
Juergen Bulitta, M.Sc.
Research Scientist
IBMP - Institute for Biomedical and Pharmaceutical Research
Paul-Ehrlich-Strasse 19
90562 Nurnberg - Heroldsberg
Germany
From: "Mats Karlsson" mats.karlsson@farmbio.uu.se
Subject: RE: [NMusers] Interpreting IOV
Date: Fri, 16 Sep 2005 08:20:46 +0200
Dear Pete,
It would be easier to say if something about the drug and study population
and study circumstances was known. Changing protein binding or blood
composition (w/ or w/o food), and different levels of physical activity
could be explanations. On the other hand it could always be modeling
nonsense.
Best regards,
Mats
--
Mats Karlsson, PhD
Professor of Pharmacometrics
Div. of Pharmacokinetics and Drug Therapy
Dept. of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
SE-751 24 Uppsala
Sweden
phone +46 18 471 4105
fax +46 18 471 4003
mats.karlsson@farmbio.uu.se
From: mark.e.sale@GSK.COM
Subject: Re: [NMusers] Interpreting IOV
Date: Fri, 16 Sep 2005 08:59:00 -0400
Pete,
Standard medical problem, don't ask a question (get a lab test) if you
don't know what you're going to do with the answer. Is this any different
from testing the hypothesis that clearance is a function of astrological
sign? Every once in a while (1 in 20) the answer will be yes. But, there
are a few physiological explanations, including changes in protein binding
- due to other drugs perhaps? or change in fluid status (due to inactivity
of confinement?).
Mark Sale M.D.
Global Director, Research Modeling and Simulation
GlaxoSmithKline
919-483-1808
Mobile
919-522-6668
From: jeffrey.a.wald@gsk.com
Subject: Re: [NMusers] Interpreting IOV
Date: Fri, 16 Sep 2005 10:25:47 -0400
Hi Peter - An important piece of information that was left out was whether
Vss was also varying between occasions. Depending on the PK profile of
your drug, sampling schedule, infusion duration*, etc you may have
difficulty resolving V1 and V2, but still have the same Vss. What is the
correlation of the V1 V2 estimates? Have you tried parameterizing the
model with IOV on Vss?
Jeff
*i.e., all iv administrations are 'infusions', but not all PK studies will
resolve a short duration infusion of say 30 sec or less :)
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