Guidance for Industry: Safety Testing of Drug Metabolites

Name of Guidance: Guidance for Industry: Safety Testing of Drug Metabolites

Status of Guidance: Final

Release Date: 14 February 2010

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf

Target Audience: Individuals/companies developing non-clinical safety evaluation plans for new chemical drug products.

Laws and Regulations Referenced: Good Laboratory Practices (21 CFR part 58). GLPs are the general regulations that apply to the conduct of all nonclinical studies to be submitted for evaluation by the FDA. GLPs set standards for operations, animal care and use, documentation, key personell, and quality assurance.

Summary: Metobolic profiles should be identified prior to initiation of human clinical trials using human and animal in vitro models and in vivo methods early in the development process. Significant differences between human and animal in vitro and in vivo metabolite investigations can signal the need for safety evaluations of just the metabolite. Analytical methods for synthesizing and qualifying the metabolite for direct administration to animals and bioanalytical methods for measuring systemic exopsure must be developed.

When it is determined that additional metabolite safety ecaluations are needed, standard nonclincal safety evalutaions should be performed. General toxicity studies should be performed at multiples of human exposure to the metabolite in order to collect relavent toxicokinetic data. Standard genotoxitiy tests that evalutate mutations and chromosamal aberrations should also be performed. A complete genotoxocity battery is only necessary if positive results are obtaine from one or both of the intitial tests. Developmental toxicity studies should be performed in at least one species if the drug is intended for use in women of child bearing potential. Carcinogenicity studies should be performed when the parent drug is intended for long term (6+ months) or intermitant long term use.

Rationale: The standard approach to nonclinical drug safety testing compares systemic exposure of investigational drug products in animal models to exposure in humans to assess the risks applicable to humans. Due to differences in drug metabolism between species, metabolites of drug products can be formed in humans that do not form in animals. When metabolites of the drug product are formed only in humans or in significantly larger proportions in humans than in animals, safety assessments in animals must be performed to assess potential risks of the metabolite in humans. Further safety assessments of metabolites are not necessary if the metabolite was formed in at least one species during assessments of the parent drug at greater than 10% of parent systemic exposure.

Resulting Recommendations: The timing and extent of the nonclinical safety evaluations of dispropportionate drug metabolites should be determined as early in the drug development process as possible. Careful consideration of the exposure to drug metabolites in several species should be made when determining additional safety evaluations. If the indication of the parent drug is for a life threatening condition with limited or no other treatment options, the extent of metabolite testing may be reduced with adequate consideration by review agencies.

Impact: The formation of drug metabolites can complicate the nonclinical safety evaluation requirements for the parent drug. For parent drugs with more than one disproportionate metabolite, additional testing can be costly and create significant developmental delays, which is why early determination of metabolic profiles is important for designing a complete development plan. Safety testing of metabolites is necessary determine toxicities and pharmacology.