Metabolite safety testing

Unique Human Metabolites The FDA metabolite safety testing guidance indicates that the unique human metabolite(s) should be considered for safety assessment in animals, especially those that have pharmacological activity or associated with a structural alert. However, there are some situations where a full set of safety studies for unique human metabolites may not be necessary, such as if the metabolite is very minor in human plasma or it is only found in human feces. 

Recent US FDA guidance on safety testing of drug metabolites [5] highlights the importance of measuring major metabolites in human and toxicological species. This increased scrutiny on the role of metabolites in the evaluation of efficacy and safety will lead to increasing demand for metabolites as analytical standards. 

US Food Drug Adminstration (2008) Guidance for Industry, Safety Testing of Drug Metabolites, http //www.fda. gov/cder/guidance/index.htm (last access October 2008). 

From the perspective of the pharmaceutical industry, the attention given to metabolites started to increase when the Pharmaceutical Research and Manufacturers of America (PhRMA) commissioned a review of the role of metabolites in dmg induced toxicity. This group, called the metabolites in safety testing (MIST) committee, partnered with the U.S. Food and Drug Administration, convened several... 

TABLE 1.6. Recent Publications/Events on Metabolite in Safety Testing... 

PhRMA—Commissioned a survey of current practices in dealing with metabolites in safety testing... 

Several workshops held to discuss metabolites in safety testing approaches across pharmaceutical industry and the expectations from FDA. 

FDA—Draft Guidance on Safety Testing on Drug Metabolites is Published... 

Mentions that a formal guidance on the issue of drug metabolites in safety testing is warranted. 

FDA—Guidance on Safety Testing on No major changes to recommendations Drug Metabolites is Published provided in the Draft Guidance. 

Figure 1.33. A decision tree flow diagram describing some of the studies needed to detennine safety of a human drug metabolite. (Food and Drug Administration (2008). Guidance for Industry Safety Testing of Drug Metabolites.)...

FDA s guidance on safety testing on drug metabolites (Food and Drug Administration, 2008), Metabolites that form chemically reactive intermediates can be difficult to detect and measure because of their short half-lives. However, they can form stable products (e.g., glutathione conjugates) that can be measured and, therefore, may eliminate the need for further evaluation. ... 

Food and Drug Administration (2005). Draft Guidance for Industry Safety Testing of Dmg Metabolites, http //www.fda.gov/ohrms/dockets/98fr/2005d-0203-gdl0001.pdf (June, 2005). 

Pmeksaritanont, T., Lin, J. H. et al. (2006). Complicating factors in safety testing of drag metabolites Kinetic differences between generated and preformed metabolites. Toxicol. Appl. Pharmacol. 217(2) 143-152. 

Smith, D. A. and Obach, R. S. (2005). Seeing through the mist abundance versus percentage. Commentary on metabolites in safety testing. Drug. Metab. Dispos. 33(10) 1409-1417. 

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Three of the human metabolites of donepezil have not undergone extensive safety tests in animals. These comprise two O-demethylated derivatives and an N-oxidation product. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. The rate of metabolism of donepezil is slow and does not appear to be saturable. These findings are consistent with the results from formal pharmacokinetic studies which showed that donepezil and/or its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin... 

FDA Draft Safety Testing of Drug Metabolites (Guidance for Industry June 2005)... 

Baillie TA, Cayen MN, Fouda H et al. (2002) Drug metabolites in safety testing. Toxicol Appl Pharmacol 182 188-196... 

Although there is currently a lot of research to replace the preclini-cal safety tests in animals with in vitro high throughput methods, so far success is limited to some metabolite and genetic toxicity screens. These methods have not been accepted yet by the regulatory authorities in the various countries as valid alternatives to animal tests. The reason is that in these screening assays too many false results are obtained to accept them as the only basis for safety assessments. 

FDA. Draft Guideline for industry Safety testing of drug metabolites. US FDA, CDER June 2005. 

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