Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports

Abstract

One Sentence Summary: Statistical associations between measured and predicted in vitro bioactivities at human proteins and adverse events of drugs were quantified while taking into account drug plasma concentrations Abstract:Adverse drug reactions (ADRs) are undesired effects of medicines that can harm patients and are a significant source of attrition in drug development. ADRs are anticipated by routinely screening drugs against secondary pharmacology protein panels. However, there is still a lack of quantitative information on the links between these off-target proteins and the risk of ADRs in humans. Here, we present a systematic analysis of associations between measured and predicted in vitro bioactivities of drugs, and adverse events (AEs) in humans from two sources of data: the Side Effect Resource (SIDER), derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System (FAERS), derived from post-marketing surveillance. The ratio of a drug's in vitro potency against a given protein relative to its therapeutic unbound drug plasma concentration was used to select proteins most likely to be relevant to in vivo effects. In examining individual target bioactivities as predictors of AEs, we found a trade-off between the Positive Predictive Value and the fraction of drugs with AEs that can be detected, however considering sets of multiple targets for the same AE can help identify a greater fraction of AE-associated drugs. Of the 45 targets with statistically significant associations to AEs, 30 are included on existing safety target panels. The remaining 15 targets include 8 carbonic anhydrases, of which CA5B was significantly associated with cholestatic jaundice. We include the full quantitative data on associations between in vitro bioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.

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“…We previously analyzed such relationships themselves [50] when considering the ratio of bioactivity against a target relative to unbound plasma concentration, with respect to the likelihood of a drug showing adverse events for annotations from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) [51] and the database SIDER [17] . The hypothesis is that if the blood plasma concentration of a drug is above the threshold needed to act on a particular target, then one would assume to see a particular type of side effect (or, more generally, biological effect).…”