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In order to test the safety of drug metabolites, I base myself on the
following Guidance: "Guidance for Industry, Safety testing of drug
This guidance describes the different scenarios to be considered for
evaluating the safety of drug metabolites. Mainly, the conduct of
further toxicity studies depends on the difference in metabolite
levels between animals and man.
In the introduction of this guidance, it is stated that "This
guidance defines major metabolites primarily as those identified in
human plasma that account for greater than 10 percent of drug related
material (administered dose or systemic exposure whichever is less)
and that were not present at sufficient levels to permit adequate
evaluation during standard nonclinical animal studies."
From this guidance, I understand that I have to determine which
metabolites are major ((3) 10% of the parent) in humans based on
either the administered dose or the ratio of systemic exposure
(AUCmetabolite/AUCparent) (see statement above). I understand very
well how to determine the % of each metabolite relatively to the
parent drug based on the administered dose. However, I'm not really
comfortable with the second criteria that is based on the ratio of
AUCs (metabolite/parent). In fact, I'm not sure that the ratio of
AUCs could be determined simply based on collection of plasma
concentrations for the parent and the metabolite since the AUC of the
metabolite depends on the fraction of the dose transformed into
metabolites (fm) and also on the metabolic clearance (CLm). May be
it's very simple, but I appreciate having your input!
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The following message was posted to: PharmPK
This draft guidance is fairly new and has certainly
raised a lot of discussion within the pharmaceutical
industry. Many companies had provided
feedback/comment to FDA. Among the many issues under
debate regarding this draft, one is the definition of
'major' metabolite, and further more, the
toxicological relevance of stable, circulating
metabolites, especially for low dose drugs. There is
a recent publication in DMD 33:1409 that may just
address your question below. Pharma industry has
certainly expressed some different perspectives and
supposedly there will be a FDA/PhRMA workshop in Dec
this year to further discuss this guideline.
Lilian Li, Ph.D.
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In addition to the comment by Lillian Li below, it is instructive to
consider the comments made by FDA at the FDA/ PhRMA workshop in Nov
2000 that formed a basis for the subsequent Baillie et al article. At
this meeting Joe De George (then at FDA) talked about the definition
of "major" metabolite or possibly even "important" metabolite, and
stated that FDA did not have a simple cut-and-paste definition of
"major". And regardless of the subsequent Baille article there still
is not at FDA a clear cutoff (e.g., 10%). It is and will always be a
situation of "case-by-case" at FDA (and certainly with some
individual FDA pharm/tox reviewers) that 10% is not a magic number,
and, in my opinion, with good reason. The reason relates to
pharmacologic or toxicologic activity. Consider, for example, a
metabolite that is 8% (relative or absolute abundance) but is
pharmacologically 10x more potent than the parent. Is that not
possibly important? If I was at FDA it would be. As to toxicologic
activity, well, that is indeed much harder to identify, but if you
have data suggesting that a metabolite at 8% has significant toxicity
associated with it, then you had better consider it "major".
(Suppose, for example, you have different metabolite abundances in 2
diff species and a serious toxicity in one species with high
abundance of a metabolite. You might in this case infer that the
metabolite may have special toxicity compared to the parent.) This
idea of considering pharmacologic/ toxicologic activity - or atleast
other things besides just abundance - seems to be implied somewhat in
the abstract below.
When you do talk to FDA about your metabolites, maybe you will find
that the reviewer for your particular drug likes the simplicity of
10%; in this case he/she is chosing to use an approach that allows
for ignoring a metabolite that is at a level "below regulatory
concern". I would expect that to be the minority of reviewers.
Rather, you should be prepared to get a reply from some reviewers
that 10% is scientifically not a magic number. And also, I think we
can expect FDA to get more conservative about this (and many other
things) rather than less conservative.
Of course, this can get very messy and expensive. Suppose you have a
parent metabolized to 4 metabolites (or more), all at 8% abundance
and all pharmacologically active? Be prepared in this case to do a
lot of work and spend a lot of resources characterizing this situation.
L. Jack Roger, Ph.D., D.A.B.T.
SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON
METABOLITES IN SAFETY TESTING Dennis A. Smith, and R. Scott Obach
Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc., Sandwich,
Kent, United Kingdom (D.A.S.) and Groton, Connecticut (R.S.O.)
Recent attention has been given to the potential roles that
metabolites could play in safety evaluations of new drugs. In 2002, a
proposal was published on "metabolites in safety testing" ("MIST")
[T. A. Baillie, M. N. Cayen, H. Fouda, R. J. Gerson, J. D. Green, S.
J. Grossman, L. J. Klunk, B. LeBlanc, D. G. Perkins, and L. A.
Shipley (2002) Toxicol Appl Pharmacol 182:188-196], which suggested
some guidelines regarding when it is necessary to provide greater
assessment of the safety of metabolites. However, this proposal was
based on relative abundance values, i.e., the percentage that a
metabolite comprises of total exposure to drug-related material. In
the present commentary, we propose that absolute abundance criteria
be used rather than relative abundance. The absolute abundance of a
metabolite in circulation or excreta in humans should be combined
with other information regarding the chemical structure of the
metabolite (e.g., similarity to the parent drug, presence of
chemically reactive substituents) and potential mechanisms of
toxicity (e.g., suprapharmacological effects, secondary
pharmacological effects, nonspecific effects). Decision trees are
described that can be used to address human metabolites in safety
Address correspondence to: Dennis A. Smith, Pharmacokinetics,
Dynamics, and Metabolism, Pfizer, Inc., Sandwich, Kent, UK CT13 9NJ.
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