Safety Testing Metabolites

As a pharmaceutical scientist involved in characterization and safety testing of drug metabolites, I enjoyed the symposium organized by Fred Guenge rich and Nick Meanwell at the last ACS national meeting. While reading the subsequent C&EN article,"Troubling Drug Metabolites," a misstatement became apparent (C&EN, Aug. 31, page 27). C&EN paraphrases Food & Drug Administration official Aisar Atrakchi as saying FDA guidance states that any human drug metabolite formed at greater than 10% concentration of the parent drug compound circulating in the blood is subject to separate safety testing.

What Atrakchi said was "human metabolites that account for greater than 10% of parent plasma exposure at steady state become a safety concern" and "if that circulating human metabolite is formed in at least one toxicological animal test species at exposure levels greater than or equal to the exposure in humans, then it can be assumed that its safety has been adequately assessed and no separate safety testing is warranted." Atrakchi's statement at the symposium is consistent with her published article (Chem. Res. Toxicol. 2009, 22, 1217) and FDA guidance. The safety testing of metabolites can be less troubling if all pharmaceutical scientists get correct and consistent information on this subject.

Ragu Ramanathan
Princeton, N.J.