Interpretation and Considerations on the Safety Evaluation of Human Drug Metabolites

Abstract

The final Food and Drug Administration guidance on the safety testing of drug metabolites was published in February 2008. Discussions of the role and applications of this guidance were addressed at several public scientific meetings over the past year. One of the main differences between the draft and the finalized guidance is that in the latter, the human metabolite level was correlated to the parent drug level in plasma, whereas this parameter was considered in relationship to administered dose or total exposure in the draft guidance. The parent drug concentration in plasma has traditionally been the parameter commonly measured in animals during drug development and the one used to estimate drug clinical levels and to assess human risk. Moreover, circulating parent drug in general is the molecule with the intended therapeutic and pharmacologic effect. Therefore, it is appropriate to compare metabolite concentration to that of the parent drug. This report elaborates on this issue and supports other alternative rational and scientific approaches on the design of nonclinical studies that may be needed to test a human drug metabolite.

Assessment of a Micropatterned Hepatocyte Coculture System to Generate Major Human Excretory and Circulating Drug Metabolites

“…It is also critically important to compare the main metabolism pathways of a new drug candidate in humans versus animals, because laboratory animal species are used in safety evaluations. It is expected that major human metabolites are represented in animal safety studies; i.e., that each human metabolite which is present in circulation at 10% or more of the total drug-related material will be present in at least one animal species that is used in safety evaluations at equal or greater exposure levels (Atrakchi, 2009;Robison and Jacobs, 2009; International Conference on Harmonization, http://www.ich.org/cache/compo/276-254-1.html). Such expectations have been described in regulatory guidance and are laid out to ensure that the human metabolites of new drugs have been adequately tested for safety.…”

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

“…Additionally, stable isotope labeling might be necessary for the validation of bioanalytical LC-MS/MS assays if a relevant metabolite needs to be monitored in clinical studies. In cases where the exposure of a metabolite in animal studies does not approach human exposure (so-called disproportionate metabolites 10 ) or when a metabolite is exclusively formed in humans (human unique metabolite 11 ) large quantities up to several kilograms may be required for nonclinical toxicological studies.…”