FDA Guidance Urges Metabolite Testing Early In Drug Development Process

A new FDA guidance encourages evaluation of metabolites as early in the drug development process as is feasible, as metabolites that appear only in human plasma or at disproportionately higher levels in humans than in animals will require nonclinical toxicity studies and such studies should be done before large-scale clinical trials.

Titled "Safety Testing of Drug Metabolites," the final guidance addresses when and how to identify and characterize drug metabolites that require further nonclinical safety assessment. It states that human metabolites that raise a safety concern are those formed at greater than 10 percent of parent drug systemic exposure at steady rate.

"Early identification of disproportionate drug metabolites can provide clear justification for nonclinical testing in animals, assist in interpreting and planning clinical studies, and prevent delays in drug development," the guidance states. "If toxicity studies of a drug metabolite are warranted, studies should be completed and study reports provided to the FDA before beginning large-scale clinical trials."

Identify Metabolites Early

The guidance notes that identification of metabolite concentrations can be accomplished at different stages of the drug development process using in vitro and in vivo methods.

In vitro metabolism studies should be conducted before initiation of clinical trials. In vivo results should be available early in the development process, as their results will either confirm the in vitro results or reveal quantitative and/or qualitative differences in metabolism across species.

"Human in vivo metabolism studies usually have been performed relatively later in drug development, but we strongly recommend in vivo metabolic evaluation in humans be performed as early as feasible," the guidance states.

To Test Or Not To Test?

When the metabolic profile in humans is similar to that in at least one of the animal species used in nonclinical studies, the typical testing paradigm (comparing drug plasma concentration and systemic exposure in the nonclinical studies to that in humans to assess potential risk) is usually sufficient, according to the guidance.

But, the guidance notes, "there are cases when clinically relevant metabolites have not been identified or adequately evaluated during nonclinical safety studies."

A metabolite is a compound derived from the parent drug through Phase I and/or Phase II metabolic pathways. Metabolites formed in Phase I reactions are more likely to need safety evaluation, as they are more likely to be chemically reactive or pharmacologically active and thus cause unintended effects.

This is particularly concerning when such a metabolite is formed only in humans and not in the animals used in safety testing. The guidance notes, however, that the problem more commonly will be that the metabolite is formed in both subjects, but at disproportionately higher levels in humans.

"If at least one animal test species forms this drug metabolite at adequate exposure levels (approximately equal to or greater than human exposure), as determined during toxicology testing of the parent drug, it can be assumed that the metabolite's contribution to the overall toxicity assessment has been established," the guidance states.

It also notes that demonstrating that a metabolite is pharmacologically inactive at the target receptor does not guarantee that it is not toxic or preclude it from nonclinical toxicity studies.

Guidance Offers Two Approaches

The guidance lists two approaches that can be considered to assess drug metabolites, when necessary.

The first is to investigate a drug's toxicity in an animal species routinely used in toxicity studies that forms the metabolite at adequate exposure levels (equivalent to or greater than the human exposure). If a relevant animal species cannot be found, the second approach would be to synthesize the drug metabolite and directly administer it to the animal for further safety evaluation.

FDA acknowledges complications with the second approach, including that direct dosing of a metabolite to animals may lead to subsequent metabolism that may not reflect the clinical situation, and that new and different toxicities may arise from administration of the metabolite that were not observed with the parent drug.

However, "identification and evaluation of the potential toxicity of the drug metabolite is considered important to ensure clinical safety."

The agency says to consider the following factors when designing a nonclinical study for a disproportionate drug metabolite: similarity of the metabolite to the parent molecule; pharmacological or chemical class; solubility; stability; stability in stomach pH; Phase I versus Phase II metabolite; and relative amounts detected in humans versus the amounts detected in animals.

The guidance says studies of general toxicity, genotoxicity, embryo-fetal development toxicity and carcinogenicity may have to be conducted to assess the safety of a metabolite.

General toxicity studies enable a comparison between the metabolite and its parent drug. The guidance says dosing and route of administration should be parallel to that used in humans.

The potential genotoxicity of the drug metabolite should be assessed in an in vitro assay that detects point mutations, and in another assay that detects chromosomal aberrations, the guidance instructs.

Embryo-fetal development toxicity should be conducted with the drug metabolite when a drug is intended for use in a population that includes women of childbearing potential.

Carcinogenicity studies "should be conducted on metabolites of drugs that are administered continuously for at least six months, or that are used intermittently in the treatment of chronic or recurrent conditions when the carcinogenic potential of the metabolite cannot be adequately evaluated from carcinogenicity studies conducted with the parent drug," the guidance states.

The agency will modify on a case-by-case basis the number and type of nonclinical studies for the metabolites of drugs to treat serious or life-threatening diseases other than cancer (e.g., ALS, stroke, HIV).

- Jamie Hammon ([email protected])