Executive Summary

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed, consisting of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level; these different levels then determine four different systems therapeutics categories. Both of these two processes are initiated by their own sets of initiators or drivers, i.e., a pharmacologic agent and an intrinsic operator, for the pharmacologic and pathophysiologic processes, respectively. The systems therapeutics framework further suggests that the wide variability in therapeutic response characteristics to approved drugs is contributed to by variabilities in both of these two processes. Examples are provided for each of the four systems therapeutics categories, and a glossary is provided for the individual systems components.

Contents:

• Executive Summary
• Introduction
• Systems Therapeutics Diagram
• Systems Therapeutics Categories
• Discussion
• References
• Glossary

Introduction

While a large number of new drugs have been approved by regulatory agencies over the past several decades, and we have witnessed significant scientific advances in molecular understanding of pharmacologic mechanisms and disease processes, there have only been sporadic efforts towards the construction of frameworks for understanding how pharmacologic and pathophysiologic processes interact to produce therapeutic effects. One noteworthy effort was presented by Grahame-Smith & Aronson in the Oxford Textbook of Clinical Pharmacology and Drug Therapy, which describes the chain of events linking the pharmacologic effects of drugs to their clinical effects, including several examples (1). An earlier effort by this author on drug classification of drug action based on therapeutic effects  was published in 1996 (2). More recent efforts have included a comprehensive white paper on quantitative and systems pharmacology by Sorger et al. of the QSP Workshop Group, including recommendations (3).

The purpose of this paper is to present a systems therapeutics framework, depicting pharmacologic and pathophysiologic processes separately, thus enabling the illustration of the different biologic levels of interactions between these two processes, and including definitions and examples. We hope this framework will be useful when examining the different types of therapeutic effects and discussing sources of variabilities in therapeutic effects. This paper on systems therapeutics summarizes and updates three previous iterations on a systems therapeutics framework posted on the Therapeutics Research Institute’s website, between April 2015 and October 2016 (4,5,6).

Systems Therapeutics Diagram

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce in a clinical therapeutic response (see diagram below; click for a larger diagram).

The systems therapeutics diagram presented above consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level. The systems components for pharmacologic processes start with a pharmacologic response element, followed by a pharmacologic mechanism, a pharmacologic response, and a clinical effect, whereas the systems components for pathophysiologic processes start with an etiologic causative factor, followed by a pathogenic pathway, a pathophysiologic process, and a disease manifestation. The four different biologic levels of interactions between these two processes then determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level), and Category IV (at the clinical level), as previously outlined (4).

Both of these two processes are initiated by their own sets of initiators or drivers, i.e., a pharmacologic agent and an intrinsic operator, for the pharmacologic and pathophysiologic processes, respectively. On the pharmacologic processes side, a pharmacologic agent, interacting with a pharmacologic response element, and its concentration or exposure, is an undisputed fundamental driver of pharmacologic processes. On the pathophysiologic processes side, a hypothetical intrinsic operator is proposed as an integral systems component interacting with and influencing an etiologic causative factor, and serving as a driver of pathophysiologic processes. This hypothetical intrinsic operator is intended to cover different biologic entities being identified using advanced bioinformatics and network-based approached, as previously presented (5,6).

The culminating result of the interaction between these two activated processes, independent of the biologic levels of interactions, involves a clinical therapeutic response. While it is well recognized that there is a wide variability in the clinical therapeutic response of individual patients to a given approved drug (7,8), it is less well recognized that both of these two processes, pharmacologic and pathophysiologic, have their inherent variabilities. This systems therapeutics construct thus further suggests that inter-patient variabilities in both of these active processes contribute to and thus are co-determinants of the ultimate patient therapeutic response characteristics, including range and extent of response, response variability, and responder rate. Presently, however, the relative contributions of each of these process variabilities to the ultimate therapeutic response are typically unclear, most significantly due to limited availability of data and methods, and are likely to vary from one therapeutic class to another. A general commentary on variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression) was previously provided (5).

Brief descriptions of the different systems therapeutics components are provided in the glossary below, including examples for each component.

Systems Therapeutics Categories

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

• Category I – Molecular Level: Elements/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: Elements/Factors

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves the primary corresponding molecular entities, the pharmacologic agent (or the pharmacologic response element) and the etiologic causative 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:

Molecular-based Therapy

• Enzyme replacement therapy, e.g., Elaprase (idursulfase) for Hunter Syndrome
• Protein replacement therapy, e.g., Recombinate (recombinant Factor VIII) for Hemophilia A
• Potentiation of defective protein, e.g., Kalydeco (ivacaftor) for Cystic Fibrosis
• Inhibition of abnormal enzyme, 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), e.g., Lipitor (atorvastatin) for Hypercholesterolemia
• Modulation of glucose metabolism (biguanides), e.g., Glucophage (metformin) for Type-2 Diabetes
• TNF-a Inhibitors, e.g., Humira (adalimumab) for Rheumatoid Arthritis
• Inhibition of microtubule polymerization, e.g., Colcrys (colchicine) for Gout

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

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

Category IV – Clinical Level: Effects/Manifestations

Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves an effect directed at clinical 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, e.g., Tylenol (acetaminophen) for lowering high body temperature
• Analgesics, e.g., Advil (ibuprofen) for Ostoearthritis
• Antihistamines, e.g., Allegra (fexofenadine) for allergic symptoms
• Antitussives, e.g., Delsym (dextromethorphan) for cough suppression

Discussion

The systems therapeutics framework presented here has been constructed with the goal of serving to facilitate understanding and discussion of the different types of successful therapies involving approved drugs. Importantly, this framework shows the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a singular pharmacotherapeutic process, and thus illustrating at what biologic level the pharmacologic process engages with the pathophysiologic process.

The systems therapeutics diagram consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, thus determining four different systems therapeutic categories. The two initiators or drivers of these two processes are also depicted, one actual (pharmacologic agent), the other hypothetical (intrinsic operator). Our rationale for the latter is based on recent bioinformatics and network-based approaches indicating that disease initiation can involve interactions between genetic and non-genetic components, although major research efforts are needed to elucidate the nature of these interactions.

The examples provided here for the different systems therapeutic categories above, as well as those provided for the individual systems components under the glossary below, are being put forward to illustrate application of the systems therapeutics framework, recognizing that some of the examples still remain provisional, pending more detailed understanding and knowledge about the mechanisms involved. Furthermore, we hope improved infographics approaches to better illustrate the proposed systems therapeutics approach will make it more useful and insightful.

It is our hope that the systems therapeutics framework presented here will help stimulate work towards better understanding of the relationships between the biologic levels of interactions between pharmacologic and pathophysiologic processes on one hand and the therapeutic response characteristics of approved drugs on the other. We also hope that this framework will stimulate research towards better qualitative and quantitative descriptions of the pharmacologic and pathophysiologic processes, including ways of defining the relative contributions of these two processes towards determining the overall therapeutic response characteristics.

References

1. Grahame-Smith DG, Aronson JK (1992). Oxford Textbook of Clinical Pharmacology and Drug Therapy, Oxford University Press, Oxford (Chapter 5. The Therapeutic Process, pp. 55-66).
2. Bjornsson TD (1996). A classification of drug action based on therapeutic effects. J. Clin. Pharmacol., 36:669-673.
3. Sorger PK, Allerheiligen SRB, Abernethy DR, et al. (2011). 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 (pp. 1-47).
4. Therapeutics Research Institute. Systems Therapeutics: A Diagram and Four Categories, April 2015. https://tri-institute.org/niDFW
5. Therapeutics Research Institute. Systems Therapeutics: Variabilities, May 2016. https://tri-institute.org/TyQij
6. Therapeutics Research Institute. Systems Therapeutics: Updated Diagram, October 2016. https://tri-institute.org/S2j9D
7. Rowland M, Tozer TN (2011). Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, Fourth edition, Lippincott Williams & Wilkins, Philadelphia (Chapter 12, Variability, pp. 333-356).
8. Eichler HG, Abadie E, Breckenridge A, Flamion B, Gustafsson LL, Leufkens H, Rowland M, Schneider CK, Bloechl-Daum B (2011). Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat. Rev. Drug Disc., 10:495-506.

Glossary

Note the examples chosen below are from among approved treatments and diseases that have been addressed in individual posts on the Therapeutics Research Institute’s website, TRI-institute.org, either in individual posts or annual reports. At this time, separate examples (high-level) are provided for pharmacologic processes and pathophysiologic processes for individual systems components. 

Pharmacologic Processes

Pharmacologic Agent 
A compound, could be a small molecule or a large bio-pharmaceutical, that initiates the pharmacologic process by interacting with a pharmacologic response element. Examples:

• Nexium (esomeprazole), and
• Viagra (sildenafil)

Pharmacologic Response Element
A native biologic element, could be a receptor or an enzyme, with which a pharmacologic agent interacts (pharmacologic interaction). Commonly referred to as a pharmacologic target. Examples:

• H+/K+ ATPase or proton pump; and
• cGMP-specific phosphodiesterase type 5 or PDE5.

Pharmacologic Mechanism
Molecular mechanism of action, typically involving a molecular pathway resulting in a biochemical reaction (signal transduction). Examples:

• Inhibition of proton pump (for Acid Reflux and Ulcer Disease); and
• Inhibition of PDE5 (for Male Erectile Dysfunction).

Pharmacologic Response
Pharmacologic effect at the tissue/organ level mediated through a pharmacologic mechanism (pharmacodynamics). Examples:

• Decreased gastric acid secretion resulting in decreased acidity (by proton pump inhibitor); and
• Smooth muscle relaxation in corpus cavernosum leading to increased blood flow (by PDE5 inhibitor).

Clinical Effect
A pharmacologic effect at the clinical level, which is the basis for a therapeutic effect (translation). Examples:

• • Decreased symptoms from gastric acidity (by proton pump inhibitor); and
• Increased erection (by PDE5 inhibitor).

Pathophysiologic Processes

Intrinsic Operator
A hypothetical entity interacting with and influencing an etiologic causative factor, serving as a driver of a pathophysiologic process. Could be genetic or non-genetic.

Etiologic Causative Factor
A genetic or non-genetic factor, upon interaction with an intrinsic operator (disease preindication), determines a disease specific progression. Examples:

• Dihydrotestosterone (DHT)-induced growth factors and their receptors (in Benign Prostatic Hyperplasia, BPH); and
• Post-menopausal and age-related osteoporosis is initiated by a developing imbalance between net bone formation and resorption (in Osteoporosis).

Pathogenic Pathway
Molecular pathogenic pathway mediating ongoing disease progression (disease initiation). Examples:

• DHT-induced growth factors stimulate proliferation of stromal cells (in BPH); and
• The normally regulated bone remodeling process is modulated by numerous systemic factors (in Osteoporosis)

Pathophysiologic Process
Ongoing pathophysiologic process (pathogenesis). Examples:

• Formation of  discrete hyperplastic nodules in periurethral region (in BPH); and
• Gradual and continuing loss of bone mineral density, decreased bone quality, with increased risk of fracture (in Osteoporosis)

Disease Manifestation
Development of characteristic clinical signs and symptoms associated with a given disease (progression), typically independent of a specific etiologic causative factor. Examples:

• Lower urinary tract symptoms (in BPH); and
• Loss of bone mineral density and bone fracture (in Osteoporosis).

Therapeutic Response
Therapeutic benefit of a drug on which approval is based, showing a beneficial change in specific objective and/or subjective measures of a disease.