A Regulatory Perspective on Issues and Approaches in Characterizing Human Metabolites

Abstract

This document captures the current thinking within FDA/CDER on the non-clinical safety assessment of human drug metabolites in new drug products. Examples are provided, which define a scientific based approach to the safety evaluation of human metabolites in new drug candidates. A discussion of the need for, and the adequacy of, the assessment of human drug metabolites with specific regard to their potential as mediators of toxicity is presented from a regulatory perspective.

Metabolite Generation via Microbial Biotransformations with Actinomycetes: Rapid Screening for Active Strains and Biosynthesis of Important Human Metabolites of Two Development-Stage Compounds, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101) and Dasatinib

“…gov/cder/guidance). Standard testing paradigms for ensuring the safety of drug metabolites have been recently proposed, and aspects of these proposals were recently reviewed (Davis-Bruno and Atrakchi, 2006;Guengerich, 2006;Humphreys and Unger, 2006;Smith and Obach, 2006; http://www.fda.gov/cder/guidance). Considerable effort is often required to prepare sufficient quantities of key mammalian metabolites of drug candidates for biological activity evaluation or for use as analytical standards.…”

A decade of drug metabolite safety testing: industry and regulatory shared learning

“…These nonclinical studies are conducted at doses in excess of the intended therapeutic dose in humans in order to establish safety margins to undesirable effects. Consequently, the safety of such novel metabolite(s) would not be adequately explored in animals by toxicology studies conducted with the parent drug even at much higher doses [1,2].…”

The synthesis of selected phase II metabolites – Ο-glucuronides and sulfates of drug development candidates

“…4 In order to assess potential safety concerns related to drug metabolism, the US Food and Drug Administration (FDA) has recently published the industry guidance "Safety Testing of Drug Metabolites" 5 which requires identification 6 of metabolite profiles and further toxicological testing 7 for those metabolites formed at greater than 10% of parent drug systemic exposure at steady state. 8 In the guidance the FDA acknowledges difficulties associated with the synthesis of specific drug metabolites, but nevertheless considers the identification and evaluation of the potential toxicity to be important to ensure patient safety. Consequently, there is a high demand for efficient, robust, and reliable drug metabolite syntheses through from milligram to gram scale.…”