Systems pharmacology, pharmacogenetics, and clinical trial design in network medicine

Abstract

The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of clinical medicine and pharmacology. Principles of systems pharmacology can be applied to drug design and, ultimately, testing in human clinical trials. Rather than focusing exclusively on single drug targets, systems pharmacology examines the holistic response of a phenotype‐dependent pathway or pathways to drug perturbation. Knowledge of individual pharmacogenetic profiles further modulates the responses to these drug perturbations, moving the field toward more individualized (‘personalized’) drug development. The speed with which the information required to assess these system responses and their genomic underpinnings is changing and the importance of identifying the optimal drug or drug combinations for maximal benefit and minimal risk require that clinical trial design strategies be adaptable. In this paper, we review the tenets of adaptive clinical trial design as they may apply to an era of expanding knowledge of systems pharmacology and pharmacogenomics, and clinical trail design in network medicine. WIREs Syst Biol Med 2011 DOI: 10.1002/wsbm.1173This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Translational, Genomic, and Systems Medicine > Translational Medicine

Precision medicine in cardiology

“…The use of predictive enrichment strat egies for trials in cardiovascular disorders is anticipated to increase pari passu with advances in systems biology, net work medicine, and the new taxonomic classifications of disease that emerge from such advances 38,41 . Investigators will then be able to move beyond the present, fairly simple approach of dose adjustment of cardiovascular agents that are based predominantly on pharmacokinetic/pharmaco dynamic data 38 , and transition into using a response surface methodology for drug adjustment as originally conceived by Lewis B. Sheiner >2 decades ago [70][71][72] (FIG. 4).…”

Saving and Improving Lives in the Information Age

“…23 A typical development program takes ≈15 years, with 10 000 compounds originally screened for 1 compound that makes it to regulatory approval. And all this costs about US $1 billion.…”

“…17 The novel oral anticoagulants were developed through a targeted and expensive approach. 23 Obviously, we cannot rely on either method to find effective new therapies. We need innovative and new approaches that do not require chance delivery of tainted hay or billion-dollar projects that span 2 decades.…”

“…25 It would be useful to focus drug discovery on a systems medicine approach. 23 Here, one synthesizes a network of information from genetic, molecular, and cellular studies and constructs a model that predicts an individual patient's response to treatment, streamlining future testing. We may then extend the observations to subgroups who have a similar profile and ultimately pool that information to develop a picture of how a population of patients might need a range of customized treatments.…”

Clinical Research and the Development of Medical Therapeutics

“…The modifications can occur at 3 levels: enrollment criteria, the characteristics of the treatment arms, and the endpoints and analyses for the trial. 12 Consider 4 different doses of an experimental treatment that are compared with a control therapy. At the interim analyses, the response to the various doses of the experimental arms is evaluated and only those that appear promising are continued, while the others are dropped.…”