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PathFX provides mechanistic insights into drug efficacy and safety for regulatory review and therapeutic development.

ABSTRACT: Failure to demonstrate efficacy and safety issues are important reasons that drugs do not reach the market. An incomplete understanding of how drugs exert their effects hinders regulatory and pharmaceutical industry projections of a drug's benefits and risks. Signaling pathways mediate drug response and while many signaling molecules have been characterized for their contribution to disease or their role in drug side effects, our knowledge of these pathways is incomplete. To better understand all signaling molecules involved in drug response and the phenotype associations of these molecules, we created a novel method, PathFX, a non-commercial entity, to identify these pathways and drug-related phenotypes. We benchmarked PathFX by identifying drugs' marketed disease indications and reported a sensitivity of 41%, a 2.7-fold improvement over similar approaches. We then used PathFX to strengthen signals for drug-adverse event pairs occurring in the FDA Adverse Event Reporting System (FAERS) and also identified opportunities for drug repurposing for new diseases based on interaction paths that associated a marketed drug to that disease. By discovering molecular interaction pathways, PathFX improved our understanding of drug associations to safety and efficacy phenotypes. The algorithm may provide a new means to improve regulatory and therapeutic development decisions.

SUBMITTER: Wilson JL

PROVIDER: S-EPMC6285459 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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PathFX provides mechanistic insights into drug efficacy and safety for regulatory review and therapeutic development.

Wilson Jennifer L JL Racz Rebecca R Liu Tianyun T Adeniyi Oluseyi O Sun Jielin J Ramamoorthy Anuradha A Pacanowski Michael M Altman Russ R

PLoS computational biology 20181207 12

Failure to demonstrate efficacy and safety issues are important reasons that drugs do not reach the market. An incomplete understanding of how drugs exert their effects hinders regulatory and pharmaceutical industry projections of a drug's benefits and risks. Signaling pathways mediate drug response and while many signaling molecules have been characterized for their contribution to disease or their role in drug side effects, our knowledge of these pathways is incomplete. To better understand al ...[more]

PMID: 30532240

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Project description:Immune thrombocytopenia (ITP) is an autoimmune disorder that induces a decrease in the number of circulating platelets due to spleen destruction and inability of megakaryocytes to restore normal counts. Immunosuppressive therapy with glucocorticoid drugs constitutes the first line of treatment. However, lack of response to these agents is not uncommon, and the management of refractory patients is a matter of controversy. In fact, day-to-day clinical practice shows that, in spite of the current guidelines, splenectomy, which is currently considered a suitable second-choice therapy, is being replaced by treatment with thrombopoietin receptor agonists. These boost platelet production by megakaryocytes. The use of one of these, namely eltrombopag, has been permitted for ITP patients refractory to first-line drugs or splenectomy, for the last 10 years. This review summarizes the experience reported using eltrombopag in ITP, paying attention to efficacy and safety. Results from clinical trials will be discussed, and studies performed in the course of daily clinical practice will also be reviewed, as these are useful to assess the potential of the drug in real-world settings. The management of adverse events and the use of eltrombopag in particular situations will also be covered. The experience reported so far permits us to suggest that eltrombopag efficiently induces recovery of platelet counts. Furthermore, recent papers have demonstrated that a sustained response after discontinuation, initially thought to be problematic, may be possible in a nonnegligible number of cases. The safety profile is satisfactory, although patients presenting with thromboembolism risk factors should be treated with caution until the eltrombopag-associated prothrombotic risk is fully established. In summary, although larger studies are still needed to clarify some issues, eltrombopag may be a useful alternative tool for ITP patients refractory to conventional medical management or splenectomy.

Dataset Information

PathFX provides mechanistic insights into drug efficacy and safety for regulatory review and therapeutic development.

Publications

PathFX provides mechanistic insights into drug efficacy and safety for regulatory review and therapeutic development.

Similar Datasets

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