Systems Pharmacology
defined as the design or use of a drug to either: i) simultaneously interact with multiple functionally- related targets that act together, or ii) inhibit targets that differ functionally from the primary target of the drug to produce additional advantageous effects for the individual patient22. Our understanding of human complexity delin-
eated by system biology studies combined with recognition of drug promiscuity and polypharma- cology led to the advent of ‘systems pharmacolo- gy’. This latter approach requires a comprehensive molecular/cellular profile of the healthy individu- al/population (systems biological profile), the dis- eased individual/population (systems pathobiolog- ical profile) and the corresponding response of the individual/population to a drug (systems pharma- cological profile). The resultant comparative datasets from systems biology versus systems pathobiology analyses and the corresponding drug effects profile constitutes a systems pharmacology approach. In addition the differences between these various states of the patient/population are referred to as ‘systems response profiles’23. A schematic representation is captured in Figure 1. As can be seen the fundamental principles for the one-drug-one target model are essentially the same as a systems pharmacology approach. However at the systems level a multitude of targets, biomarkers and diagnostic components are all considered. The resultant effect is a more comprehensively-defined health/disease/adverse framework of the individual /population as well as a safer, more efficacious drug. Systems pharmacology is predicated on the
polypharmacology of therapeutic drugs. So what is the difference between the two terms? They are both used as descriptors to describe efforts to over- come the one drug-one target model. Polypharma- cology refers to a one drug-multi-target concept as utilised in drug repurposing1. However, systems pharmacology refers to a broader concept best cap- tured as one drug-multi targets associated with pathways and networks. Thus systems pharmacol- ogy is based on the rational design of drug thera- pies using information based on molecular, cellular and physiological complexity. This type of approach produces systems pharmacology drugs rooted in molecular interactions between a single drug and multi-targets present in defined path- ways/networks.
Combination therapy versus systems pharmacology drugs We have discussed above the limitations of the one drug-one target compound that includes safety/
Drug Discovery World Winter 2018/19
toxicity and side-effect issues as well as limited effi- cacy. In the case of multi drug-multi-targets (ie combination therapy) such an approach is designed to elicit synergistic effects brought about by different mechanisms of action by more than a single drug. In this context, systems pharmacology is a one drug-multi-target model combined with pathway/network analysis that should significantly enhance efficacy and reduce safety/toxicity effects. Anighoro et al have suggested that while there is “…highly significant therapeutic relevance of com- bination therapies, [there are] potential advantages of a targeted therapy based on a single drug that modulates the activity of multiple targets over sin- gle-targeted or combination therapy”33. Some of the advantages of systems pharmacology drugs over combination therapies include:
i A single systems pharmacology drug with multi- target activity may have a more predictable, there- fore superior pharmacokinetic (PK) profile com- pared to a number of individual drugs adminis- tered in combination. ii Acute toxicity may be enhanced in more non- selective combination therapies. iii Adverse synergistic effects may be more pro- nounced in combination therapies. iv The probability of developing target-based resis- tance to multi-target drugs is statistically lower than is the probability of developing resistance against single-target drugs. v The administration of a single systems pharma- cology drug results in a more consistent and pre- dictable ADME profile. vi Drug-drug interactions do not exist in a systems pharmacology regime. vii A single agent binding to multiple targets might be easier to develop given that the regulatory requirements showing safety/efficacy of a drug combination.
For all these reasons, the development of single
drugs with a desired multi-target profile defined by pathway/network analysis do offer a com- pelling, cost-effective alternative to drug combi- nations. Historically, drug combination therapy has been more extensively explored in the clinic than the use of single multi-target drugs. However, both approaches are likely to yield sin- gle drugs or drug combinations with improved safety and efficacy profiles. In either case, key to success will likely be the informed selection of suitable biological targets and molecular path- ways/networks that need to be modulated with drug molecule(s)33.
Continued from page 37
9 ProCon,Org Thirty-Five FDA-approved Prescription Drugs Later Pulled from the Market. http://prescription
drugs.procon.org/view.resourc e.php?resourceID=005528. 10 Vizirianakis, IS (Ed). Handbook of Personalized Medicine: Advances in Nanotechnology, Drug Delivery and Therapy. CRC Press/Taylor Francis Group. Boca Raton, FL, USA. (2013). 11 Spear, BB, Heath-Chiazzi, M and Huff, JJ. Clinical Applications of Pharmacogenetics. Trends Mol. Medicine 7, 201-204 (2001). 12 Naylor, S. NostraPharmus Revisited: Splendid Isolation or Multifactorial Participation for the Pharmaceutical Industry? Drug Discov. World. Summer Supplement. 10-12 (2010). 13 Naylor, S. Technology: Bane or Bonanza for the Pharmaceutical Industry. Drug Discov. World. Fall Edition. 51- 57 (2007). 14 Davidov, EJ, Holland, J, Marple, E and Naylor, S. Advancing Drug Discovery through Systems Biology. Drug Discovery Today, 8, 175-181 (2003). 15 Naylor, S. Systems Biology, Information, Disease and Drug Discovery. Drug Discov. World. Winter Edition. 23-31 (2004/2005). 16 Culbertson, AW, Valentine, SJ and Naylor, S. Personalized Medicine: Technological Innovation and Patient Empowerment or Exuberant Hyperbole? Drug Discov. World. Summer Edition 18-28 (2007). 17 Naylor, S and Chen, SY. Unraveling Human Complexity and Disease with Systems Biology and Personalized Medicine. Personal. Med. 7. 275-287 (2010). 18 Naylor, S. What’s in a Name? The Evolution of “P- Medicine”. J. Precision Med. 2, 15-29 (2015).
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