Lhasa Limited shared knowledge shared progress
Publications

Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and postmarketing reports

Smit IA; Afzal AM; Allen CHG; Svensson F; Hanser T; Bender A;

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 reporting 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, derived from clinical trials, and the Food and Drug Administration Adverse Event Reporting System, derived from postmarketing surveillance. The ratio of a drug’s therapeutic unbound plasma concentration over the drug’s in vitro potency against a given protein 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 9 carbonic anhydrases, of which CA5B is significantly associated with cholestatic jaundice. We include the full quantitative data on associations between measured and predicted in vitro bioactivities and AEs in humans in this work, which can be used to make a more informed selection of safety profiling targets.

Download

Additional Documents

    © 2021 Lhasa Limited | Registered office: Granary Wharf House, 2 Canal Wharf, Leeds, LS11 5PS, UK Tel: +44 (0)113 394 6020
    VAT number 396 8737 77 | Lhasa Limited is registered as a charity (290866)| Company Registration Number 01765239 (England and Wales).

    Apart from the free survey software, we also have access to QuestionPro's free survey templates . We've found many of them useful and powerful to collect insights from various stakeholders of our organization.