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Dear All,
I was reviewing the literature on interspecies scaling of monoclonal
antibodies, and I've noticed a variation in the reported allometric
exponent for clearance ("b" in Y=a*W^b). Mordenti et.al. lead off
with a review of five proteins, finding an exponent of b=0.74 for an
CD4-IgG [1]. Lin et.al. examined a VEGF-IgG and found b=-0.21 (0.79
when transformed, I believe) [2]. These examples follow the classical
thinking that the typical clearance exponent is b=0.75.
In contrast, Richter et.al. found an allometric exponent of b=1.06 for
lenercept [3]. Khor et.al. found a similar exponent of b=0.93 for
PSGL-Ig [4]. Most recently, Kelley et.al. found an exponent of b=1.01
for SGN-40 [5]. These references suggest that a b=1.0 may be
appropriate for some antibodies.
I would interpret this to mean that antibodies vary considerably in
this aspect. Would my colleagues care to comment on what may be going
on here? Lacking studies in multiple preclinical species, I'm having
a hard time with a priori selection of the clearance allometric
exponent for a novel antibody.
Warm Regards
Mike Dodds
References:
1. Mordenti J, Chen SA, Moore JA, Ferraiolo BL, Green JD.
Interspecies scaling of clearance and volume of distribution data for
five therapeutic proteins. Pharm Res. 1991 Nov;8(11):1351-9.
2. Lin YS, Nguyen C, Mendoza JL, Escandon E, Fei D, Meng YG, Modi NB.
Preclinical pharmacokinetics, interspecies scaling, and tissue
distribution of a humanized monoclonal antibody against vascular
endothelial growth factor. J Pharmacol Exp Ther. 1999 Jan;288(1):371-8.
3. Richter WF, Gallati H, Schiller CD. Animal pharmacokinetics of the
tumor necrosis factor receptor-immunoglobulin fusion protein lenercept
and their extrapolation to humans. Drug Metab Dispos. 1999 Jan;27(1):
21-5.
4. Khor SP, McCarthy K, DuPont M, Murray K, Timony G.
Pharmacokinetics, pharmacodynamics, allometry, and dose selection of
rPSGL-Ig for phase I trial. J Pharmacol Exp Ther. 2000 May;293(2):
618-24.
5. Kelley SK, Gelzleichter T, Xie D, Lee WP, Darbonne WC, Qureshi F,
Kissler K, Oflazoglu E, Grewal IS. Preclinical pharmacokinetics,
pharmacodynamics, and activity of a humanized anti-CD40 antibody
(SGN-40) in rodents and non-human primates. Br J Pharmacol. 2006 Aug;
148(8):1116-23. Epub 2006 Jul 10. Erratum in: Br J Pharmacol. 2007 Jan;
150(2):248.
--
Mike Dodds, PhD
PK/PD, Pre-clinical Development
ZymoGenetics, Inc.
1201 Eastlake Avenue
Seattle, WA, 98102, USA
Email: doddsm.at.zgi.com
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The following message was posted to: PharmPK
Mike,
The allometric exponent for clearance parameters is 3/4 (by well
established theory and experimental data). Other estimates should be
considered as errors arising from studies that are not powered to
detect differences from the theoretical value.
Please see this reference for further details:
Anderson BJ, Holford NH. Mechanism-Based Concepts of Size and Maturity
in Pharmacokinetics. Annu Rev Pharmacol Toxicol 2007
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-at-.auckland.ac.nz
www.health.auckland.ac.nz/pharmacology/staff/nholford
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Mike
I believe that the examples you cite reflect the now commonly accepted
notion that there is no single "right" value for the b exponent when
dealing with clearance, or for that matter with any other PK metric.
Body size can obviously be expected to be one of the factors affecting
pharmacokinetics but why would anybody expect it to be the only or the
most dominant factor. Since the weight of these factors in determining
the PK may vary from compound to compound, a wide range of b values
is only to be expected for most PK metrics. Therefore allometric
prediction errors may range between 1 - orders of magnitude and I am
not aware of any generally applicable approach to determine a priori
how accurate will allometric scaling be for your compound or whether
the values of the allometric parameters will resemble those observed
for other compounds.
Zvi Teitelbaum
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Dear All
> "The allometric exponent for clearance parameters is 3/4 (by well
established theory and experimental data). Other estimates should be
considered as errors arising from studies that are not powered to
detect differences from the theoretical value."
This is a very bold and incorrect statement disproved by the very
publication cited immediately after, where the authors cite allometric
coefficients for several drugs with extreme values such as 0.53 and
0.87 with 95% CI of .47-.59 and .64-1.1 respectively. We should not
confound empirical numerical relationships with scientific theory.
An allometric extrapolation will always be that: an extrapolation. It
should be used to guide a prospective study acknowledging always the
fact that only when experimental evidence is gathered, conclusions
should be made.
Cheers
Luis
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA 02115
Luis.Pereira.at.bos.mcphs.edu
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The following message was posted to: PharmPK
Nick
Your reference - to your own paper - is off by 1 year.
It is Annual Review of Pharmacology and Toxicology
Vol. 48 (Volume publication date February 2008)
First posted online on October 3, 2007
Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics
Meyer
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Dear Mike,
The feature of monoclonal antibodies PK is that it is often nonlinear,
consisting of linear part that stems from general catabolism of the
protein, and nonlinear part (Michaelis-Menten type) stemming from
target-mediated clearance. Scaling of the linear pathway can generally
be reflected by standard allometric equations (and is probably more
precise than for small molecules since differences in metabolism
between species do not mess it up). Scaling of the nonlinear part is
dependent on comparative abundance of the target, turnover rates of
the target and binding affinity to the target between the species -
very target and species dependent thing. Also, because of nonlinear
behavior, clearance calculated by noncompartmental methods will give
different results depending on where concentrations are compared to Km
(from Michaelis-Menten). So, the net effect, i.e. power coefficient,
if standard allometric regression is used based on noncompartmental
calculations, could be anywhere.
Hope this helps,
Katya
--
Ekaterina Gibiansky
Director, PK/PD
Clinical Development
MedImmune, Inc.
GibianskyE.aaa.MedImmune.com
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Dear Mike,
We have quite a good history in the use of various monoclonals in man,
and therefore know the disposition characteristics of non-specific
IgG. Therefore for scaling, the key point is to take into account the
specific binding characteristics. This requires four pieces of
information: i) localisation of the target, is it in the systemic
circulation or on a cell surface in a tissue? ii) The molar expression
level and iii) turnover of the target; will binding to it affect,
quantitatively, the disposition of the monoclonal, perhaps through
internalisation and destruction in lysosomes, or even just acting as a
"peripheral compartment" the size of which varies with target
expression. And finally, iv) the affinity of binding. By far the
majority of effort to predict the PK of monoclonals in man should be
spent on characterising the target.
I gave a presentation at this year's AAPS NBC on this topic, complete
with a beautiful example of a target mediated disposition. The slides
are available to download:
http://www.aapspharmaceutica.com/meetings/files/86/PhilipLowe.pdf
The companion lecture on target mediated disposition by Don Mager is
also well worth viewing
http://www.aapspharmaceutica.com/meetings/files/86/DonaldEMager.pdf
Best regards, Phil.
Senior fellow, Modelling & Simulation
(Specialist in physiological PK & PD, drug-ligand binding & cross-
species extrapolation)
Novartis Pharma AG, WSJ-027.1.22, CH-4056 Basel, Switzerland
phil.lowe.-at-.novartis.com
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