Background

While a large number of drugs have been approved by FDA over the past seven to eight decades, and there have been significant recent scientific advances in molecular and genomic understanding of diseases, there have only been sporadic efforts towards the construction of frameworks for understanding how pharmacologic and pathophysiologic processes interact to produce a therapeutic effect. One early noteworthy effort is presented in the Oxford Textbook of Clinical Pharmacology and Drug Therapy, which describes the chain of effects linking the pharmacologic effects of drugs to their clinical effects, including several examples.[1] More recent efforts have included a comprehensive white paper on quantitative and systems pharmacology by the QSP Workshop Group, including recommendations.[2] The purpose of this paper is to present a systems therapeutics diagram, which we hope can be useful when examining the different types of therapeutic effects, illustrating the different levels of interactions between pharmacologic and pathophysiologic processes.

Systems Therapeutics Diagram

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact, resulting in a clinical therapeutic effect (see diagram below; for a larger diagram click here). The high-level systems therapeutics diagram presented here describes four different levels of interactions, involving corresponding locations along the pharmacologic and pathophysiologic process axes, ranging from the molecular level, through the cellular and tissue/organ levels, to the clinical level. These four different levels of interactions are referred to as systems therapeutics categories.

Systems Therapeutics Categories

The systems therapeutics diagram presented lends itself to propose four systems therapeutics categories, corresponding to the four different levels of interactions between pharmacologic processes and pathophysiologic processes, as follows:

• Category I – Molecular Level: Targets/Factors
• Category II – Cellular Level: Mechanisms/Pathways
• Category III – Tissue/Organ Level: Responses/Processes
• Category IV – Clinical level: Effects/Manifestations

A further description of each of these systems therapeutics categories is provided below, including definitions and examples of pharmacologic classes and approved drugs for each.

Category I – Molecular Level: Targets/Factors

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves the primary corresponding molecular entities, the therapeutic agent and the etiologic factor, respectively.

Examples – These can involve replacement therapies (hormones, enzymes, proteins, genes) or genome-based therapies (interference with altered gene products), resulting in a therapeutic effect:

Replacement Therapy

• Enzyme Replacement Therapy, e.g., Elaprase (idursulfase) for Hunter Syndrome
• Gene Therapy, e.g., Glybera (alipogene tiparvovec) for Familial Lipoprotein Lipase Deficiency

Genome-based Therapy

• Potentiation of a defective transport protein (CFTR), i.e., Kalydeco (ivacaftor) for Cystic Fibrosis
• Inhibition of altered enzyme (BCR-ABL tyrosine kinase), e.g., Gleevec (imatinib) for Chronic Myelogenous Leukemia (CML)

Category II – Cellular Level: Mechanisms/Pathways

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves a fundamental biochemical mechanism, related to the disease evolution, although not necessarily an etiologic pathway.

Examples – These can involve metabolism-based therapies (interference with a biochemical mechanism or a disease network-linked pathway), resulting in a therapeutic effect:

Metabolism-based Therapy

• HMG-CoA Reductase Inhibitors (statins) for Hypercholesterolemia, e.g., Lipitor (atorvastatin)
• Biguanides for Type-2 Diabetes, e.g., Glucophage (metformin)
• TNF-a Inhibitors for Rheumatoid Arthritis, e.g., Humira (adalimumab)
• Inhibition of microtubule polymerization for Gout, e.g., Colcrys (colchicine)

Category III – Tissue/Organ Level: Responses/Processes

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves a modulation of a normal physiologic function, linked to the disease evolution, although not necessarily an etiologic pathway.

Examples – These can involve function-based therapies (modulation of a normal physiologic function or activity), resulting in a therapeutic effect:

Function-based Therapy

• PDE-5 Inhibitors for Male Erectile Dysfunction, e.g., Cialis (tadalafil)
• Angiotensin II Blockers for Hypertension, e.g., Avapro (irbesartan)
• Proton Pump Inhibitors for Gastric Reflux & Ulcer Disease, e.g., Nexium (esomeprazole)
• Factor Xa Inhibitors for Thrombosis, e.g., Eliquis (apixaban)

Category IV – Clinical Level: Effects/Manifestations

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves an effect directed at symptom(s) of a disease, but not directly its cause or etiology.

Examples – These can involve symptom-based therapies (various symptomatic or palliative treatments), resulting in a clinical therapeutic effect

Symptom-based Therapy

• Antipyretics for lowering high body temperature, e.g., Tylenol (acetaminophen)
• Analgesics for pain, e.g., Advil (ibuprofen)
• Antihistamines for allergy, e.g., Allegra (fexofenadine)
• Antitussives for cough suppression, e.g., Delsym (dextromethorphan)

Discussion

The systems therapeutics framework presented above, including a diagram and four categories, has been constructed with the goal of serving to facilitate discussion and understanding of the different types of successful therapies involving FDA approved drugs. Importantly, this framework attempts to illustrate both the pharmacologic processes and the pathophysiologic processes, rather than exhibiting a singular pharmacotherapeutic process, in contrast to previous attempts, highlighting at what level the pharmacologic process engages with the pathophysiologic process. It is noted that this systems-based framework does not explicitly address interpatient variability in therapeutic response.

The examples listed above for the different systems therapeutics categories are provisional, pending more detailed descriptions of the pivotal interactions, including graphics ways to illustrate these. One important point this approach demonstrates and highlights is that many successful therapies are not directed at a specific known cause or etiology of a disease. However, it needs to be emphasized that the diagram and categories presented here represents work in progress, and that there are undoubtedly many other ways to accomplish our goal regarding systems therapeutics.

It is well recognized that there is considerable inter-patient variability in both pharmacologic processes and pathophysiologic processes (in addition to pharmacokinetic variability) – pharmacodynamic and “pathodynamic” variabilities – neither one of which is explicitly incorporated into the systems therapeutics framework presented here. Yet, these processes clearly represent the determinants of the overall variability in therapeutic response and clinical outcome of a given therapeutic agent, a topic of significant interest given the variable therapeutic response characteristics of approved drugs. We also note that our understanding of the “drivers” of these processes is limited, and that attempts to date to delineate these have been mostly descriptive, underscoring the necessity for much needed research.

This project of Systems Therapeutics is one of three current projects of the Therapeutics Research Institute, in addition to Progression of Modern Therapeutics and Patient Therapeutic Response Characteristics. It is our hope that the framework presented will help stimulate work towards better understanding of the relationships between the levels of interactions between pharmacologic and pathophysiologic processes on one hand and the therapeutic response characteristics of approved drugs on the other.

References

[1] Grahame-Smith DG, Aronson JK. Oxford Textbook of Clinical Pharmacology and Drug Therapy, Oxford University Press, Oxford, 1992 (Chapter 5. The Therapeutic Process, pp. 55-66).

[2] Sorger PK, Allerheiligen SRB, Abernethy DR, et al. Quantitative and systems pharmacology in the post-genomic era: New approaches to discovering drugs and understanding therapeutic mechanisms. An NIH white paper by the QSP workshop group. Bethesda: NIH, October 2011 (pp. 1-47)