Using human experience to identify drug repurposing opportunities: theory and practice

Abstract

Retrospective evidence drawn from real-world experience of a medicine's use outside its labelled indication is one of a number of techniques used in drug repurposing (DRP). Relying as it does on large numbers of real incidences of human experience, rather than individual case reports with limited statistical support, preclinical experiments with poor translatability or in silico associations, which are early-stage hypotheses, it represents the best validated form of DRP. Cancer is the most frequent of such DRP examples (e.g. aspirin in pancreatic cancer, hazard ratio = 0.25). This approach can be combined with pathway analysis to provide first-in-class treatments for complex diseases. Alternatively, it can be combined with prospective preclinical studies to uncover a validated mechanism for a new indication, after which a repurposed molecule is chemically optimized. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 680-689 680 with cognitive dysfunction treated with metformin, to determine the relative benefit in situations involving vascular dementia relative to Alzheimer disease. Although case reports are often the bases for repurposing hypotheses, they lack statistical rigour and, for the purposes of this review, are not included in the definition of retrospective human evidence Retrospective data for drug repurposing Br J Clin Pharmacol (2019) 85 680-689 681 Retrospective data for drug repurposing Br J Clin Pharmacol (2019) 85 680-689 683 Retrospective data for drug repurposing Br J Clin Pharmacol (2019) 85 680-689 689

Repurposed Antimicrobial Combination Therapy: Tobramycin-Ciprofloxacin Hybrid Augments Activity of the Anticancer Drug Mitomycin C Against Multidrug-Resistant Gram-Negative Bacteria

“…The dearth of available therapeutics to treat MDR Gram-negative bacterial infections has energized the scientific community to seek newer approaches and ingenious strategies. Instead of de novo development that are typically capital- and time- intensive, repurposing FDA-approved non-antibiotic drugs for antimicrobial therapy has recently gained significant traction as a method of discovery (Polamreddy and Gattu, 2018; Cavalla, 2019; Gns et al, 2019). We wondered whether anticancer agents could be repurposed as antimicrobials to eradicate MDR Gram-negative bacteria.…”

“…Promising strategies have emerged including anti-virulence therapy (Dickey et al, 2017), phage therapy (Kortright et al, 2019) and multicomponent combination therapy (Tyers and Wright, 2019). Repurposing non-antibiotic drugs for antimicrobial therapy offers a cost- and time-efficient method of discovery (Rangel-Vega et al, 2015; Soo et al, 2017; Polamreddy and Gattu, 2018; Cavalla, 2019). This is advantageous since the agents under study have well-characterized pharmacokinetic parameters and have undergone the rigorous process of safety evaluation from health agencies such as the United States’ Food and Drug Administration (FDA) (Gns et al, 2019).…”

Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma

“…Rapta-C, an experimental ruthenium (II)-based compound, binds to the histone proteins in chromatin, exploiting favorable anti-cancer activity, further demonstrated to be favorable for drug combination studies [35]. Intending to identify drugs that might interact synergistically in combination with Rapta-C, we selected eleven repurposed drugs, based on the following criteria: (i) reported anti-cancer activity; (ii) validation via the ReDo project [14]; (iii) literature information [4,6,7,13,15,69,70]; and (iv) known combinations with cisplatin or with ruthenium(II)based compounds (Table S1).…”

Proteomics and Drug Repurposing in CLL towards Precision Medicine

“…Furthermore, through in silico approaches, there is the possibility to understand the pathobiology and development of lymphoid tumors in detail, using data that is already available. The disadvantages of in silico approaches are the reduced reproducibility of the results, in some cases due to the different algorithms and the constantly updating versions, the production of false positive and negative results and consequently, the unsuccessful translation of the results into clinical practice [ 130 , 131 , 132 , 133 , 134 ]. Conversely, the advantage of the in vitro drug repurposing is the tangible proof of the effective action of drugs in an experimental disease model, which consists of the first step of translation into clinical practice.…”

“…Effective candidate pharmaceutical agents are first selected from bioinformatic data analyses and then validated for their proposed action and efficacy on in vitro meticulously selected disease models. The ultimate goal of this double-stranding approach is to unravel the pathobiology and development of the disease through the in silico approach, as well as to save resources and time by reducing the list of drugs needed to be tested experimentally and at the same time accelerate the translation of results into clinical practice through the experimental validation and screening of these drugs [ 131 , 134 ]. Consequently, the approach that is usually followed and considered as rationally acceptable is the following: (Omic) data collection of the disease of interest (proteomics data are preferred).…”