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Systems Pharmacology


Perspective on systems pharmacology when multi-targeting is advantageous


The safety and efficacy of therapeutic drugs still requires improvement. In part this is due to the promiscuity of individual drugs, which on average can interact with an estimated 6-28 other off-target moieties. However, the advent of both systems biology and precision medicine has stimulated a rethink on the process of therapeutic drug design and polypharmacology. More recently, the definition of polypharmacology has morphed to represent therapeutic drugs that have been designed deliberately for multi-targeting that affords beneficial effects to the patient. This emerging effort has been labelled ‘Systems Pharmacology’ and the products are referred to as multi-target or systems pharmacology drugs.


T


he current Drug Discovery and Develop- ment (DDD) paradigm was conceived in the early 1960s and has remained relatively


unchanged over the past ~60 years. We, and others, have argued that this continues to be a risk-laden, slow, costly and inefficient process, as well as deliv- ering products of questionable value in terms of safety/toxicity and efficacy1-5. For example, signifi- cant cumulative risk is associated with any effort to bring a candidate drug to market. The initial screening of compound libraries (104-106 candi- dates), leads to a single lead compound that has only an ~8% chance of successfully traversing the clinical trials gauntlet6. In addition, the failure rate of a drug candidate at each clinical trial phase is reported to be 46% (Phase I), 66% (Phase II) and 30% (Phase III)4. The average time required from drug discovery to product launch remains an eye- watering 12-15 years5. In addition, the total capi- talised cost of bringing a new drug to market was recently estimated at a staggering $2.87 billion7.


Drug Discovery World Winter 2018/19


The metrics associated with the DDD process


are clearly problematic. There is also a concern about the safety and efficacy value proposition of current marketed therapeutic drug products pro- duced by the current DDD process. In part this is due to:


i) Drug safety: Not all approved drugs stand the test of market pressures due to the scrutiny of pharmacovigiliance and post-market surveillance. In some cases approved drugs can be removed from the market because they manifest safety, effectiveness or economic problems. For example from 1994-2015, the USA Food and Drug Administration (FDA) issued 215 ‘Withdrawal of Application’ notices8. During that same time peri- od the FDA actually recalled 26 drugs from the US market predicated primarily on safety concerns9.


ii) Drug effectiveness: There is now a significant body of evidence that indicates individual patients


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By Dr Kirkwood A. Pritchard Jr, Dr Dustin P. Martin and Dr Stephen Naylor


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