Predicting Circulating Human Metabolites: How Good Are We?

Abstract

The FDA issued a guidance on the safety testing of metabolites in February 2008, in which they stated that metabolites of concern are those that are detected at levels greater than 10% of the systemic exposure of the parent at steady state. This has presented many challenges in determining the circulating human metabolites at an early stage of development. The intention of this perspective is to address the question of how effective in vitro metabolism and early exploratory clinical data are in predicting the circulating metabolites from both a qualitative and a quantitative perspective. To this end, data were reviewed from 17 molecules in the Lilly portfolio for which there were in vitro data and a radiolabeled study in humans. Twelve example cases are presented in detail to demonstrate trends for when in vitro data adequately predicted in vivo (41%), when in vitro data underpredicted the circulating metabolites (35%), and when in vitro data overpredicted the circulating metabolites (24%). In addition, cases that present special challenges due to very low levels of the circulating parent or long half-lives of the parent and/or metabolites are presented. The trends indicate that the more complex the metabolism, the less likely the in vitro data were to predict the circulating metabolites. The in vitro data were also less predictive for N-glucuronidations and non-P450-mediated cleavage reactions. Although the in vitro data were better at predicting clearance pathways, the data set often failed to predict the quantity of metabolites, which is needed in consideration of whether or not a "disproportionate" metabolite may be circulating in human plasma.

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

“…Although it was readily demonstrated that major metabolites of many compounds could be generated by in vitro systems, rates of success were generally in the range of 50%. Similar findings were made by Anderson et al (2009). Thus, there is considerable room for improvement for in vitro systems as applied to the generation of relevant human metabolite profiles.…”

Identification of Three Novel Ring Expansion Metabolites of KAE609, a New Spiroindolone Agent for the Treatment of Malaria, in Rats, Dogs, and Humans

“…The prediction of circulating metabolites in humans and why certain metabolites circulate are topics of interest in drug metabolism research, as discussed in several publications (Anderson et al, 2009;Dalvie et al, 2009;Smith and Dalvie, 2012). When species differences are observed in the disposition of metabolites, as was the case for metabolite M23 of KAE609, it may lead to the necessary safety evaluation of metabolites depending on their exposure in humans (see U.S. Food and Drug Administration 2008, guidance available at http:// www.fda.gov/cder/guidance/index.htm and http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/default.htm).…”

Prediction of Relative In Vivo Metabolite Exposure from In Vitro Data Using Two Model Drugs: Dextromethorphan and Omeprazole

“…gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm079266.pdf and www.ema.europa.eu/pdfs/human/ich/ 028695en.pdf), and the European Medicines Agency included recommendations for in vitro P450 enzyme inhibition testing of new drug metabolites (http://www.ema.europa.eu/ema/pages/includes/document/open_ document.jsp?webContentId ϭ WC500090112). These recent guidance documents have drawn attention to the development of methods for early identification of metabolites and prediction of metabolite exposures (Anderson et al, 2009;Leclercq et al, 2009).…”