4.2.2.4 — Metabolism

In vitro and in vivo metabolism studies, metabolite identification and profiling

Requirements by Phase

IND Phase 1: basic IND Phase 2: full IND Phase 3: required NDA: required

Content Requirements

• Chemical structures and quantities of metabolites in biological samples
• Possible metabolic pathways
• Pre-systemic metabolism (GI and hepatic first-pass)
• In vitro metabolism including CYP450 reaction phenotyping
• Enzyme induction and inhibition potential
• Interspecies comparison of metabolic profiles

Expected Deliverables

• Metabolite identification report
• In vitro metabolism report (CYP phenotyping)
• Metabolic pathway diagram
• Interspecies metabolite comparison table

ICH Guidelines: M3(R2)

Regulatory Requirements (FDA IND PHASE 1)

• [All phases] If known, this section should contain: 1) a description of the pharmacologic effects and mechanism(s) of actions of the drug in animals, and 2) information on the absorption, distribution, metabolism, and excretions of the drug.

Regulatory Requirements (ICH M3R2)

• [before Phase 3] Further PK information (absorption, distribution, metabolism, excretion) and in vitro biochemical information relevant to potential drug interactions should be available before exposing large numbers of human subjects or treating for long duration (generally before Phase III).

Regulatory Requirements (ICH S1A)

• [Pre-marketing approval] If similar metabolism and systemic exposure can be demonstrated by differing routes of administration, then carcinogenicity studies should only be conducted by a single route.

Regulatory Requirements (ICH S9)

• [Nonclinical/Clinical] Further information on absorption, distribution, metabolism and excretion of the pharmaceutical in animals should normally be generated in parallel with clinical development.

Note: P1: in vitro only. P2+: full characterization

Source: ICH M3(R2)