Drug Metabolites: A Regulatory Perspective on Why, How, and When to Test Their Safety

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Drug Metabolites A Regulatory Perspective on
Why, How, and When to Test Their Safety

• Aisar H. Atrakchi, Ph.D
• Division of Neuropharmacological
• Drug Products
• FDA

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Why 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.

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Why 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.

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Why 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.

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What 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.

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What 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.

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Background

• 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.

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Why 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.

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Why 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.

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Why 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.

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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.

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General 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.

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Goals 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.

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Goals 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.

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General 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

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General 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.

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Studies 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.

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Studies 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.

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Studies 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.

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Studies 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,

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Studies 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.

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Timing 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.

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