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Dear All,
I appreciate if anybody can provide the algorithm for MABEL (Minimally
Active Biological Effect Level) based on data from preclinical disease
model.
Thanks
Ayyappa
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The following message was posted to: PharmPK
Dear Ayyappa,
That's a question many of us are likely to be grappling with. So, the
short answer is likely "no": there's no simple algorithm.
The intent is to integrate in vitro, in vivo and in silico models to
provide a first-in-human dose that will provide some minimal
perturbation to the targeted system. If you have performed a
dose-ranging study in a preclinical disease model, you should have some
idea of the (saturable?) effect curve. You should also consider the
applicability of the disease model. Perhaps an exposure that provokes
5% of the maximal effect in your disease model could be scaled to human
exposure and selected as your MABEL dose?
Again, Ayyappa, this is a matter of debate in the community. I'm very
pleased that you brought this up, however. I hope the ensuing
discussion is informative for everyone.
Warm Regards,
Mike
----
Mike Dodds, PhD
PK/PD, Pre-clinical Development
ZymoGenetics, Inc.
1201 Eastlake Avenue
Seattle, WA, 98102, USA
Email: doddsm.-a-.zgi.com
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The following message was posted to: PharmPK
Ayyappa:
Can you provide references which use the term you have used: MABEL
(Minimally Active Biological Effect Level)? I have done a search using
OVID and those terms did not bring up any references for the 1997-2007
period.
Professor Walter Wolf, Ph.D.
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California
1985 Zonal Ave., Los Angeles, 90089-9121
E-mail: wwolfw.-a-.usc.edu
http://www.usc.edu/research/initiatives/bisi/
http://www.usc.edu/schools/pharmacy/faculty_directory/detail.php?id=59
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Yes, I could also find only few guidelines and powerpoint
presentations just advocating the use of MABEL dose calculation
approach, but nothing about actual methodology or calculations.In one
of presentations, they advocate use of NOAEL to calculate HED (human
equivalent dose based on body surface area) and then using most
appropriate HED to calculate MRSD (maximum recommended dose). But no
details with an example are available.
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Dear All,
See:
http://www.emea.europa.eu/pdfs/conferenceflyers/first_in_man/05-J_Sims_AstraZeneca.pdf
Yours sincerely
Ian Smith, BSc, PhD, DipRCPath (Tox).
Principal, ASIS Solutions.
E: Ismith1945.-a-.aol.com
A: 4, Greenfield Way, Cuddington, Northwich, CW8 2YH, UK
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Dear Dr. Wolf,
I have only one presentation from MABEL workshop from EMEA website and
I am trying to understand the algorithm from that. Eventhough, the
there presentation says there is no simple algorithm and it should be
case by case.
Thanks
Ayyappa
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The serious adverse events observed in TGN1412 (CD28 supra-agonist)
Phase I trial in 2006 led to re-evaluation of predictive effect of the
preclinical models. The task force and expert scientific group that
reviewed the TGN1412 trial recommended the use of
MABEL (Minimal Anticipated Biological Effect Level) for determining
the starting dose in humans. This would take into consideration of
novelty of the agent, biological potency, mechanism of action,
receptor occupancy versus concentration, degree of species
specificity, in vivo dose response data, PK/PD modelling ... and is a
broader approach for first dose calculation than NOAEL.
Refs:
http://www.abpi.org.uk/information/pdfs/BIAABPI_taskforce2.pdf
http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/.-at-.dh/.-at-.en/documents/digitalasset/dh_073165.pdf
Subsequently, Euopean medicines agency issued a guidance document
pertaining to the usage of MABEL for estimation of doses in high risk
medicinal products.
http://www.emea.europa.eu/pdfs/human/swp/2836707enfin.pdf
Hope this helps.
Ganesh
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The following message was posted to: PharmPK
Dear Walter,
I think Ayyappa is using MABEL defined in EMEA (EMEA/CHMP/SWP/28367/07),
"GUIDELINE ON STRATEGIES TO IDENTIFY AND MITIGATE RISKS FOR
FIRST-IN-HUMAN
CLINICAL TRIALS WITH INVESTIGATIONAL MEDICINAL PRODUCTS" finalized July
this year.
MABEL is "Minimal Anticipated Biological Effect Level".
Regards,
Mike Dodds
--
Mike Dodds, PhD
PK/PD, Pre-clinical Development
ZymoGenetics, Inc.
1201 Eastlake Avenue
Seattle, WA, 98102, USA
Email: doddsm.aaa.zgi.com
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The following message was posted to: PharmPK
Walter,
There isn't anything of substance on MABEL in the literature. The
concept of MABEL can be found in an EU guideline http://www.emea.europa.eu/pdfs/human/swp/2836707enfin.pdf
and a report on Early stage Clinical Trials from ABPI/BIA http://www.bioindustry.org/biodocuments/Early_Stage_Clinical_Trials_Joint_Taskforce_Report.pdf
A summary of the comments on the EU guidance can be found at http://www.emea.europa.eu/pdfs/human/swp/29519007en.pdf
Unfortunately, as was pointed out in another e-mail, none of these
documents will help you understand exactly how to calculate MABEL.
Regards
Mark Milton
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The following message was posted to: PharmPK
All,
The "Expert Scientific Group on Phase One Clinical Trials: Final Report"
explicitly walks through a number of MABEL calculations:
http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/.-a-.dh/.aaa.en/documents/digitalasset/dh_073165.pdf
Thanks for that reference, Ganesh.
There also an interesting use/reference to a traditional
agonist-receptor calculation (p. 30 of the document) that could be of
use, if your biologic has a well-defined binding target. However, it is
my contention that a two-player system (drug and target) is sometimes
insufficient when the target interacts with an endogenous player that is
highly expressed (drug, target, target's receptor).
Regards,
Mike
--
Mike Dodds, PhD
PK/PD, Pre-clinical Development
ZymoGenetics, Inc.
1201 Eastlake Avenue
Seattle, WA, 98102, USA
Email: doddsm.aaa.zgi.com
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Mark,
The final report of the expert scientific group shows an example
calculation for determining MABEL and may be helpful.
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_063117
Best,
Ganesh Mugundu
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Dear Colleagues,
MABEL should be an assessment of all available information on the
activity and exposure to a drug in preclinical species, combined with
scaling both the activity (i.e. PD) and exposure to man. It should be
a minimal biological effect level, for whatever effect, desired or
adverse. In effect, it is seeking the bottom end of a dose- or
concentration response curve, so that one can then safely escalate.
Good pharmacological practice in effect.
There is a recent publication in Xenobiotica which may be helpful. In
addition to the general treatise on anticipating the human dose, there
is a section on how to calculate a MABEL for a biologic based on
receptor theory, including the effect of receptor expression level if
that is important. This method tends to give a very conservative
assessment, much to the consternation of project teams, but at least
it does open eyes to the possibilities of activity at low dose levels.
The method in this paper was provided to the UK authority through
ABPI, is what Jenny Sims refers to in part of her presentation, and is
referred to in EMEA documents.
http://www.informaworld.com/smpp/content?content=10.1080/00498250701648008
or this URL for a direct link to the pdf if your institution has
access...
http://www.informaworld.com/smpp/
ftinterface~content=a783595319~fulltext=713240930
As Jenny points out, there are other methods for calculating MABEL
based on, for example, human cell systems suitably extrapolated to man
(with correction for unbound fractions, etc). Whichever extrapolation
gives the lowest dose should be used, unless there is strong and
relevent evidence that it would be safe to proceed with higher doses.
Monoclonal antibody binding models can also be set into kinetic
schemes to help with calculations for MABEL. An example of this was
been referred to last month in a discussion on interspecies scaling of
monoclonals. I copy the reference material here for convenience:
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
Novartis Pharma AG, WSJ-027.1.22, CH-4056 Basel, Switzerland
Phone: +41 61 324 4676; Mobile: +41 79 349 7806; phil.lowe.-a-.novartis.com
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