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I am working with a monoclonal antibody that is adminstered by
infusion for 4 hours. The only two samples collected on each visit
are at the end of infusion and 4 hours after the end of infusion. In
the vast majority of patients and on many different occasions within
a patient, the concentration 4 hours after the infusion has stopped
is higher, sometimes many ug/mL higher, than the concentration at the
end of infusion. I would normally think this is an analytical
problem but it is happening in so many patients and at multiple
visits throughout the year that I am not so sure anymore. Has anyone
seen a delay in distribution to this effect that might explain this
phenomenon or have any other ideas for why this is happening?
Thanks alot,
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.at.genzyme.com
[Not an immune response, affecting the assay?? ;-) - db]
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Hello Peter,
One thought that comes to mind is enterohepatic circulation. I'm not
familiar with MoAbs, but if they can survive the small intestine
environment, this might be an explanation. (I see a few references in a
Google search mentioning intrajejunal administration of, I think,
MoAbs).
Your initial infusion is over 4 hours, resulting in a slow
introduction of
drug to the central circulation. With enterohepatic circulation, after a
meal, the gall bladder will empty in a much shorter time (on the
order of 30
minutes). If a meal is given before the second sample is taken, and if
considerable drug is recirculated via this route, it might be absorbed
quickly enough to produce a higher peak than the initial infusion.
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.aaa.simulations-plus.com
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Hello Pete:
I would suggest two effects that can cause the 4 hour
"increase". One is that the antibody is being held in the lung for a
period and then released. Second, you may have initial targeting to one
or more antigen sinks and then have release back into the blood. The
latter can be modeled using the K on and K off rate constants. Such
alveolar and sink effects are not mutually exclusive so that both may be
operating at the same time.
Our group has experience with radiolabled antibodies of
various molecular weights. I assume your Mab is intact and has MW of
around 160 kDa. If you are describing a single chain antibody, your time
sampling is too slow to follow the actualy course of events in the
animal or patient.
Best wishes.
Larry Williams
City of Hope.
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Dear Pete:
Most likely, your observation is real. This has been
previously observed with monoclonal antibodies. I
initially observed this with some liposomal products
and after talking to my colleagues I noted it is
rather not that uncommon with monoclonal antibodies.
Please go the archive for more discussion and possible
explanation on this particularly the link below will
connect you to some the expert in this area.
http://www.boomer.org/pkin/PK02/PK2002013.html
Rostam
[Search the archive (http://www.boomer.org/pkin/simple.html) for
'Antibodies half-life determination' if the URL above changes - db]
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Hi Pete:
We have seen such Cmax delays with mAb infusions <= 1 hour and dense
sampling. IMHO, this is *partially* attributable to having
essentially similar plasma concentrations (V1 ~3 L) for many hours
due to slow distribution to Vss (~5 L) and even slower CL (~10 mL/h
for a humanized mAb), coupled with assay variability.
Tom
S.T.Forgue.aaa.Lilly.com
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Hi Pete:
We have seen such Cmax delays with mAb infusions <= 1 hour and dense
sampling. IMHO, this is *partially* attributable to having
essentially similar plasma concentrations (V1 ~3 L) for many hours
due to slow distribution to Vss (~5 L) and even slower CL (~10 mL/h
for a humanized mAb), coupled with assay variability.
Tom
S.T.Forgue.-a-.Lilly.com
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Dear Dr Bonate,
I cannot add anything to the many expert replies to your post but I was
wondering whether patient mobility (or rather immobility) during the
infusion could be a contributing factor. For example, is the patient
sitting or lying down during the 4-hr infusion and is then allowed to
move around before the second sample is taken? This could affect blood
flow through a number of tissues, which may or may not act as a sink for
the monoclonals. Reminds me of DVT on long flights to and from New
Zealand!
Kind regards,
Frederik Pruijn
Frederik B. Pruijn PhD MSc (Senior Research Fellow)
Experimental Oncology Group
Auckland Cancer Society Research Centre
Faculty of Medical and Health Sciences
The University of Auckland
Private Bag 92019
Auckland
New Zealand
Phone: +64-9-3737 599 x86939 or x86090
Fax: +64-9-3737 571
E-mail: f.pruijn.-a-.auckland.ac.nz
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Dear Dr Bonate
Does your assay measure free, bound or total fraction ?
Since volume of distribution of mAbs is so limited (usually between
plasma volume and extracellular fluids volume), it can also be
hypothetized that any delayed pharmacodynamic effect on the
vasculature may have a marked effect on the PK.
Regards,
Antoine DESLANDES, PhD
DMPK Senior Manager
CENTELION SAS
72-82 Rue Leon Geffroy
94408 VITRY SUR SEINE CEDEX
FRANCE
Phone (33).1.58.93.36.30
Fax (33).1.58.93.35.05
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)