Title: Drug Metabolites: A Regulatory Perspective on Why, How, and When to Test Their Safety
1Drug Metabolites A Regulatory Perspective on
Why, How, and When to Test Their Safety
- Aisar H. Atrakchi, Ph.D
- Division of Neuropharmacological
- Drug Products
- FDA
2Why the need for Metabolite Testing?
- Only recently increased awareness of the role of
metabolites as contributors to drug toxicity have
come to light and has been discussed in the
scientific and regulatory arenas, although - Historically, some metabolites have been shown to
be pharmacologically active (equivalent, more,
or different activity than the parent drug),
and/or toxic, and - Metabolites could be present at much higher
levels in plasma than the parent drug.
3Why the need for Metabolite Testing?
- Traditionally, only parent drug circulating
levels in animals were measured and used as an
index of systemic exposure and safety assessment
in humans. - This was partly because the contribution of the
metabolites to the overall toxicity profile of
the parent drug was unknown and, - The unavailability of sensitive analytical
methods that can detect and identify circulating
metabolites. - In the past decade, technologies have evolved
that are capable of identifying, measuring and
characterizing drug metabolites.
4Why the need for a guidance?
- The role of drug metabolites in safety assessment
was recently deliberated by a multidiscipilnary
group from the pharmaceutical industry,
academics, and regulatory agencies and this led
to the publication of the MIST paper (Metabolite
in Safety Testing)(Toxicol Appl Pharmacol, 2002), - The FDA provided a response to the MIST paper in
a Letter to the Editor and, later a decision
was made by the CDER PK subcommittee to formally
address this issue in an FDA Guidance for
Industry Safety Testing of Drug Metabolites.
5What are the Objectives of this Guidance ?
- To make recommendations on when and how to
evaluate the safety of unique or major
metabolite(s) not adequately assessed by standard
nonclinical safety studies during development of
small molecular (non-biologic) therapeutic
products. - To encourage identification of differences
between the metabolic profiles of humans and
animals as early as possible during the drug
development process. - To address circumstances where non-clinical
studies using direct administration of the unique
human metabolite may be warranted.
6What is Unique / Major human metabolites?
- Unique metabolites are those formed or detected
only in humans. - Major metabolites are those formed or detected
at much higher levels in humans than in any
animal species used during standard nonclinical
toxicology studies. - This guidance defines major metabolites as
those detected in human plasma at gt10 of drug
related material (administered dose or systemic
exposure, whichever is less) and therefore, were
not present at sufficient levels to permit
adequate safety evaluation in animal studies.
7Background
- Generally, we can assume the clinical risk
assessment profile is adequate when both in vivo
and in vitro metabolism study results are similar
across species. - However, quantitative and/or qualitative
differences in metabolic profiles and metabolite
concentrations may exist between humans and
animals as well as across animal species. When
such differences occur, it is especially
important to identify metabolites that may be
unique to humans.
8Why gt10?
- In addition to being consistent with other FDA
and EPA guidances, - There are case examples where drug metabolites
present at gt10 but lt20 contributed largely to
drug toxicity.
9Why gt10?
- Halothane-induced liver toxicity is due to its
reactive metabolite, trifluoroacetylchloride,
that represents lt20 of administered dose. This
toxicity limited the use of the drug. - The metabolites of the antiepileptic drug
felbamate that cause aplastic anemia and
hepatotoxicity, collectively account for 16 of
felbamate concentration in urine.
10Why gt10?
- The anticancer drug, cyclophosphamide, has no
direct cytotoxic action. However, toxicity is
attributed to a number of metabolites including,
4-hydroxy-cyclophosphamide, which represents 8
of the total plasma exposure. - Acetaminophen-induced hepatotoxicity is due to
its reactive intermediate, N-acetyl-p-benzoquinone
imine (NAPQI). This metabolite is detected as
thioether metablites in urine, which constitutes
9 of a therapeutic dose of acetaminophen.
11 General Considerations for Identification
of Metabolites
- Generally, demonstration that a metabolite is
inactive pharmacologically at the target receptor
does not guarantee that it is not toxic. - If major or unique metabolites are suspected to
contain a reactive functional group, the safety
of these metabolites should be investigated. - Similarly, reactive intermediates are of safety
concern even if they are generally short lived.
Stable products of these intermediates may
provide some information on exposure to these
potentially toxic species.
12General Considerations for Non-Clinical Study
Design
- The following are general characteristics for
compounds that may warrant additional
investigation - Narrow therapeutic indices.
- Significant toxicity.
- Significant diverse metabolic profiles between
human and nonclinical species. - Irresversible toxicity, or adverse effects not
readily monitored in the clinic.
13Goals Recommendations of Safety Testing
- To evaluate the General toxicity profile of the
drug and its metabolites in rodent and nonrodent
animal species and, - To assess the potential for genotoxicity in
support of - phase 1 safety and tolerability studies in
humans. - Early in vitro metabolism studies assist in
selection of the appropriate animal species for
the toxicity testing should interspecies
differences in metabolism are detected.
14Goals Recommendations of Safety Testing
- It is prudent to determine if metabolites
contribute to a clinically relevant toxicity
observed during nonclinical assessment. - Because unique human metabolites may only be
identified after completion of in vivo metabolism
studies in humans, the guidance recommends that
such evaluation be done as early as possible.
15General Considerations for Non-Clinical Study
Design
- When designing nonclinical studies for a
unique/major metabolite, the following should be
considered - Physicochemical properties,
- Patient population,
- Route and Duration of use,
- Exposures at the therapeutic dose
16General Considerations for Non-Clinical Study
Design
- Generally, systemic exposure is assessed by
measurement of compound concentration in serum or
plasma. However, other biological matrices such
as urine, feces, or bile may be considered when
measurements in plasma can not be made. - Structure Activity Relationship analyses may be
considered in predicting activity relative to a
known structural alert however, it is not a
substitute to actual testing. - It is important to consider combined exposure to
parent and pharmacologically active metabolites
in safety assessments.
17Studies Recommended for Assessing Metabolite
Safety
- General Toxicity
- Duration minimum of 14 days to a maximum of 90
days (ICH Q3B(R)). - On a case by case basis, longer duration in 2
species may be warranted e.g. metabolites more
toxic than parent, delayed and/or different
toxicity, non-moniterable toxicity or, different
target organs. - Based on the results of the general toxicity
studies, mechanistic studies may be needed to
assess specific toxicity endpoints.
18Studies Recommended for Assessing Metabolite
Safety
- In vitro assay to detect point mutation, and
- In vitro chromosomal aberrations.
- If one or both assays are equivocal and/or
positive, the complete battery of genotoxicity
studies is warranted.
19Studies Recommended for Assessing Metabolite
Safety
- Embryo-Fetal Developmental Studies
- When the intended patient population includes
women of childbearing potential, an embryo-fetal
developmental toxicity study is recommended (ICH
S5A and S5B). - On a case by case basis, other studies may be
needed.
20Studies Recommended for Assessing Metabolite
Safety
- Carcinogenicity
- Carcinogenicity assessment may be needed on a
case by-case basis for - Metabolites of drugs that are administered
chronically for at least 6 months or used
intermittently in the treatment of chronic or
recurrent conditions. - When one or more of the following is
observedgenotoxic or carcinogenic structural
alert, positive genotoxicity results, or any
other relevant data,
21Studies Recommended for Assessing Metabolite
Safety
- When it is determined that carcinogenicity
assessment is needed, then one of the following
should be done - A single 2 year rodent bioassay or
- Addition of a metabolite dose group to the
carcinogenicity study with the parent drug.
22Timing of Safety Assessment
- Sponsors are encouraged to conduct in vitro
studies to identify and characterize unique human
metabolites early in drug development. If
independent toxicological characterization of a
human metabolite is warranted, FDA recommends
these studies be completed and the study reports
be submitted prior to commencement of large-scale
Phase 3 trials. - On a case by-case basis, safety assessment of the
- unique/major metabolite may need to be
conducted earlier.
23(No Transcript)