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The following message was posted to: PharmPK
Sirs,
What would be the best way to study the pharmacokinetics of humanized
anti-interleukin antibodies injectad i-v in humans? In particular, does
anybody have experienced some blood or plasma sampling strategy in order
to determine at best the main parameters of such proteins? Does the
bound/free value have sense?
Thanks to everybody in advance.
Claude Ardiet
PK Laboratory
Centre Lˇon Bˇrard
LYON - France
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The following message was posted to: PharmPK
Dear Dr. Ardiet:
I will let others answer your main question. Howevert, one of the very
important issues you may want to have answered is what will be the
degree of targeting of the antibody to their effector site(s). And that
could be done by
radiolabeling the antibody under conditions that would not affects its
chemical or biological properties (e.g. with either 131-I or 123-I, or
with one of the radiometals following attachment of a chelator). Doing
such noninvasive imaging studies would give you answers that go well
beyond what you could learn from blood-based studies.
Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences Director,
Pharmacokinetic Imaging Program Department of Pharmaceutical Sciences,
School of Pharmacy University of Southern California
1985 Zonal Ave., Los Angeles, CA 90089-9121 E-Mail: wwolfw.-a-.hsc.usc.edu
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because iodination may alter binding and the normal structure of the
molecule that must be compared to native.
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Dr. Ardiet
One of the first questions will be whether or not the bioanalytical assay
measures free or total monoclonal antibody. If the assay measures only free
MAb, then the modeling may need a covariate to explain the initial behavior
of the time vs concentration curve where in the initial distribution phase
the free MAb is bound to the target. I've found that the majority of
humanized MAb kinetics associated with IV administration can be described by
a bolus IV two compartment model with first order elimination. Initial
estimates of the constants can be found in the literature for other MAb that
have been developed to target different interleukins (point being not to
re-invent the wheel but set the initial estimates of the PK parameters to
literature values).
On a related point, I would be curious to hear from the discussion group
regarding MAb kinetics associated with subcutaneous administration. Another
interesting point is the kinetics associated with very high dose IV
administration of MAb where the plasma concentration vs time curves show a
Cmax several hours after the bolus dose (sometimes up to 24 hr later). Any
ideas on how to model high dose data that do not fit the two compartment IV
bolus model used for low dose data?
Cheers!
Jeffrey L. Larson, Ph.D.
Director of Toxicology and Pharmacokinetics
Tanox, Inc.
4888 Loop Central Drive
Houston, TX 77081-2225
(713) 578-4212
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Jeffrey:
Do you know of any data supporting the idea that the rate of binding of
an
antibody concurs with the rate of decline in free antibody
concentrations in
vivo? This would support the idea that the initial distribution phase
of free
MAb is accounted for by binding to the target.
Michael
Michael D. Karol, Ph.D., A.R.F., R.Ph.
Associate Research Fellow
Section Manager, Clinical Pharmacokinetics
Center of Clinical Assessment
Abbott Laboratories
AP13A-3, D-R4PK
100 Abbott Park Road
Abbott Park, IL 60064-6104
Michael.D.Karol.at.Abbott.Com
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Dr. Larson,
Can you provide a reference or two with IV profiles (bolus dose) of high
dose MAb. The delayed Cmax is quite intriguing. Thanks.
Srikumaran K. Melethil, Ph.D., JD (2002)
Professor, Pharmaceutics and Medicine
University of Missouri- Kansas City
203B Katz Hall (School of Pharmacy)
Kansas City, MO 64110
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Dear Dr Larson,
if you have any general refs to pk/pd of MAb's, I would appreciate to
receive these,
thanks,
Martin W Lunnon
GlaxoSmithKline R&D
Neurology CEDD Harlow
e-mail: Martin_W_Lunnon.-a-.gsk.com
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Dr. Melethil,
At the moment, I can only lay my hands on the Summary Basis of Approval for
Remicade (search SBA on the FDA website). The clinical pharmacology section
provides curves that indicate a delay in Cmax. I also am working with an
MAb that demonstrates such a delay.
Jeffrey L. Larson, Ph.D.
Director of Toxicology and Pharmacokinetics
Tanox, Inc.
4888 Loop Central Drive
Houston, TX 77081-2225
(713) 578-4212
--
Dr. Lunnon
I have found two of the most valuable references in terms of MAb kinetics
are the Summary Basis of Approval documents for monoclonal antibodies found
on the FDA website and the Scientific Discussion documents for the European
regulatory authorites. Among these are Remicade (Infliximab), Herceptin
(Trastuzumab), Enbrel (Etanercept), Simulect (Basiliximab), and Zenepax
(Dacliximab).
In addition:
J. Pharmacol. Exp. Ther. 286:925 (preclinical anti-CD40 ligand)
J. Pharmacol. Exp. Ther. 291:1060 (preclinical anti-IL-5)
J. Pharmacol. Exp. Ther. 288:371 (preclinical antiVEGF)
Clin. Pharmacol. Ther 62:675 (clinical anti-IgE)
Jeffrey L. Larson, Ph.D.
Director of Toxicology and Pharmacokinetics
Tanox, Inc.
4888 Loop Central Drive
Houston, TX 77081-2225
(713) 578-4212
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It causes some wrestling to deal with apparent half life of Ab. For
example, most antibody assays involve measurement by binding to ligand. If
the Ab is already bound in vivo it is not measured in vitro, unless some
effort is made to disrupt binding then measure Ab in the assay. It's
Heisenburg all over again
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