Framework, Diagram, Categories, Definitions, Examples

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Thorir D. Bjornsson, MD, PhD

Therapeutics Research Institute

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Synopsis

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed to further describe such interactions, consisting of two rows of four parallel systems components for pharmacologic and pathophysiologic processes. These systems components represent the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ level, and the clinical level. Both processes have their own sets of initiators or drivers. These four different levels of pivotal interactions between these processes then determine four different systems therapeutics categories, i.e., Categories I, II, III and IV. Examples of pharmacologic classes are provided for each of these categories, and illustrative examples are provided for the interactions of each of these categories highlighting the pivotal interaction. Finally, a glossary of the systems components for pharmacologic and pathophysiologic processes is included. It is hoped that the systems therapeutics framework presented here will promote discussions regarding the need for better understanding of the determinants of therapeutic response characteristics of modern therapeutics. 

Table of Contents

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Introduction

While hundreds of 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 clinical therapeutic effects. One noteworthy effort was presented by Grahame-Smith and Aronson in the Oxford Textbook of Clinical Pharmacology and Drug Therapy, which describes the chain of events linking the pharmacologic actions of drugs to their clinical effects, including several examples (1). 

The purpose of the present work is to provide a systems therapeutics framework, depicting pharmacologic processes and pathophysiologic processes separately, thus enabling the presentation of the different biologic levels of pivotal interactions between these two processes, and thereby allowing the determination of different systems therapeutics categories.

Efforts on this project were initiated at the Therapeutics Research Institute in the mid 2010’s, although initially it was not clear how this work would evolve. The development of the systems therapeutics framework was an iterative process, most importantly in determining the number and naming of the systems components representing the different biological levels. Different iterations of this framework were produced and posted on the Therapeutics Research Institute’s website, TRI-institute.org, between 2015 and 2018, including an evolving construction of a systems therapeutics diagram, four biologic levels of interactions, four systems therapeutics categories, examples of approved drugs and pharmacologic classes for each category, relevant definitions, and illustrative examples of how the sequence of events proceeds for pharmacologic and pathophysiologic processes (2,3). The present version builds on the latest version from 2018, and includes an expanded description of the systems therapeutics diagram and an edited discussion.

Systems Therapeutics Diagram

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram, shown in Figure 1, has been constructed to describe such interactions.

The organizing principle underlying the systems therapeutics diagram involves two rows of four parallel systems components for pharmacologic processes 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 level, and the clinical level, in addition to the initiating entities or drivers of these processes and the ultimate therapeutic response.

The systems components for pharmacologic processes start with a pharmacologic response element, followed by a pharmacologic mechanism, a pharmacologic response, and a clinical (pharmacologic) 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). It is noted that these systems components represent generally recognized pharmacologic and pathophysiologic terms. Brief descriptions of the individual systems components are provided in the glossary below, including examples for each component.

Each 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 process side, a pharmacologic agent (i.e., a drug), through its concentration or exposure, interacting with a pharmacologic response element (e.g., a receptor, or so-called drug target), is the fundamental driver of pharmacologic processes. This initial interaction with the pharmacologic response element leads to initiation of a pharmacologic mechanism via signal transduction. On the pathophysiologic process side, a hypothetical intrinsic operator is proposed as an initiator or driver interacting with and influencing an etiologic causative factor, via disease preindication, and thus serving as a driver of pathophysiologic processes, while the etiologic causative factor determines the specific disease expression. The hypothetical intrinsic operator is envisioned as an endogenous entity, not external or circulating, originating in a diseased organ’s principal cell type(s). It is intended to comprise different unidentified biologic entities, to be characterized in the near future using advanced bioinformatics and network-based approaches.This initial interaction with the etiologic causative factor leads to the initiation of a pathogenic pathway via disease initiation. The etiologic causative factor represents a biomolecular entity or network determining the specific disease expression, e.g., a molecular abnormality or malfunction characterizing the disease under consideration, such as a specific genetic mutation or protein abnormality. 

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response

The next three systems components for pharmacologic processes, i.e., pharmacologic mechanism, pharmacologic response and clinical (pharmacologic) effect, first involve the sequence of effects from the cellular level to the tissue/organ level via pharmacodynamics, and then from the tissue/organ level to the clinical or whole-body level via translation. The corresponding three systems components for the pathophysiologic processes, i.e., pathogenic pathway, pathophysiologic process and disease manifestation, first involve the sequence of effects from the cellular level to the tissue/organ level via pathogenesis, and then from the tissue/organ level to the clinical or whole-body level via progression. The culminating result of the interaction between these two processes, independent of the biologic level of the pivotal interaction, involves a therapeutic response, determined by how the clinical (pharmacologic) effect moderates the disease manifestation.

It is noted that while it is well recognized that there is a wide variability in the clinical therapeutic response of individual patients to a given approved drug (4,5), it is less well recognized that both two processes, pharmacologic and pathophysiologic, have their inherent interpatient variabilities (6).

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 pivotal interactions between pharmacologic processes and pathophysiologic processes, as follows:

Category I – at the Molecular Level: Elements/Factors

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

Examples of Molecular-based Therapy – These can involve replacement therapies (hormones, enzymes, proteins) or interferences with altered gene products):

• Enzyme replacement therapy, e.g., idursulfase (Elaprase) for Hunter Syndrome
• Protein replacement therapy, e.g., recombinant Factor VIII (Recombinate) for Hemophilia A
• Potentiation of defective protein, e.g., ivacaftor (Kalydeco) for Cystic Fibrosis
• Inhibition of abnormal enzyme, e.g., imatinib (Gleevec) for Chronic Myelogenous Leukemia (CML)

Category II – at the 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 of Metabolism-based Therapy – These can involve metabolism-based therapies (interference with a biochemical mechanism or a disease network-linked pathway):

• HMG-CoA Reductase Inhibitors (statins), e.g., atorvastatin (Lipitor) for Hypercholesterolemia
• TNF-a Inhibitors, e.g., adalimumab (Humira) for Rheumatoid Arthritis
• Xanthine Oxidase Inhibitors, e.g., allopurinol (Zyloprim) for Hyperuricemia and Gout

Category III – at the 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 of Function-based Therapy – These can involve function-based therapies (modulation of a (normal) physiologic function or activity):

• Angiotensin II Receptor Blockers, e.g., irbesartan (Avapro) for Hypertension
• PDE-5 Inhibitors, e.g., tadalafil (Cialis) for Male Erectile Dysfunction
• Factor Xa Inhibitors, e.g., apixaban (Eliquis) for Thrombosis

Category IV – at the 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 of Symptom-based Therapy – These can involve symptom-based therapies (various symptomatic or palliative treatments):

• Antipyretics, e.g., acetaminophen (Tylenol) for lowering high body temperature
• Analgesics, e.g., ibuprofen (Advil) for Osteoarthritis 
• Antitussives, e.g., dextromethorphan (Delsym) for cough suppression

Illustrative Examples

Below are illustrative examples for each of the four systems therapeutics categories. The charts follow the design of the systems therapeutics diagram. The pivotal connection between pharmacologic and pathophysiologic processes represents the fundamental or primary interaction between these processes (represented by a fat arrow), thus determining the systems therapeutics category; these are followed by dependent or secondary connections to the right (represented by thin arrows). The descriptions for the individual systems components were generated from generally available textbooks of pharmacology, pathophysiology and medicine, and other sources, but with an emphasis on a separation of pharmacologic and pathophysiologic concepts and processes, culminating in a therapeutic response.

Illustrative Example for Systems Therapeutics Category I (Figure 2)

Illustrative Example for Systems Therapeutics Category II (Figure 3)

Illustrative Example for Systems Therapeutics Category III (Figure 4)

Illustrative Example for Systems Therapeutics Category IV (Figure 5)

Discussion

The systems therapeutics diagram was constructed to facilitate better understanding and discussion of the different types of successful therapies. Importantly, this framework shows the pharmacologic processes and the pathophysiologic processes separately, thus enabling illustrations at what biologic level these processes interact to produce a clinical therapeutic response. This contrasts with the commonly used single linear pharmacotherapeutics process, which is grounded in the clinical pharmacology and pharmacokinetics literature, starting with a drug dose, through concentration and pharmacologic effect, and ending in a clinical effect, thus not considering the pathophysiologic process (3). The illustrative examples presented above for the four different systems therapeutics categories provide descriptions of the two progressing processes in a storyboard-like fashion, highlighting at what biologic level the pivotal interaction occurs between these two processes.  

Systems Components of Pharmacologic and Pathophysiologic Processes – The systems components of the pharmacologic and pathophysiologic processes are the building blocks of the systems therapeutics diagram (see Figure 1 above). These were identified to allow description of the different biologic levels where interactions between the two processes occur, and thus enabling the determination of four different systems therapeutics categories. As outlined above, the systems components for both processes represent generally recognized pharmacologic and pathophysiologic terms (see definitions in Glossary below). The final systems component, the therapeutic response, is independent of the biologic level of the pivotal interaction and describes how the clinical (pharmacologic) effect moderates the disease manifestation. 

Pharmacologic processes and pathophysiologic processes can be co-determinants of the ultimate patient therapeutic response characteristics, and interpatient variability, to a specific therapeutic agent

Initiators or Drivers of Pharmacologic and Pathophysiologic Processes – In addition to the systems components for pharmacologic processes and pathophysiologic processes are the two initiators or drivers of these two processes, one actual (pharmacologic agent), the other hypothetical (intrinsic operator), respectively. The pharmacologic processes’ initiator or driver, a pharmacologic agent (a drug), is well recognized as determining the magnitude of the pharmacologic response, through its concentration and exposure, determined by biopharmaceutical and pharmacokinetic processes. On the other hand, the pathophysiologic processes’ initiator or driver, an intrinsic operator, is a hypothetical entity based in part on recent 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 (7,8). Also, an indirect rationale for proposing a hypothetical intrinsic operator derives from considerations of age of disease onset, where this entity acts on an etiologic causative factor, which determines the specific disease expression. While different diseases start clinically at different age ranges, one assumes the underlying etiologic causative mechanism has typically been in place for some time, perhaps years or decades. For example, the age of onset for schizophrenia is thought to be in early adulthood, while the age of onset for Alzheimer’s disease is thought to be in late adulthood. On the other end of the age spectrum, inborn errors of metabolism, e.g., phenylketonuria, typically occur in very early childhood, often starting at a few months of age, and acute lymphocytic leukemia typically starting in early childhood. A commonly proposed explanation to account for the differently delayed onsets of diseases involves the theory that varying durations of time are required for the pathophysiologic processes to progress before a disease becomes clinically manifest, from a few months to several decades. A hypothetical intrinsic operator, however, albeit with an unknown regulation, might prove a useful concept to better understand disease initiation and progression. In this regard one is reminded of the usefulness of hypothetical constructs in biology and disease models, e.g., the pharmacologic effect compartment in PK-PD modeling (9,10).

Interpatient Variability in Therapeutic Response – The systems therapeutics diagram by depicting pharmacologic and pathophysiologic processes separately acknowledges the potential for interpatient variability not only on the pharmacologic process side, e.g., due to drug exposure or pharmacologic response differences, but also on the pathophysiologic side, e.g., due to differences in pathogenic pathways or disease progression. Thus, pharmacologic processes and pathophysiologic processes can be co-determinants of the ultimate patient therapeutic response characteristics, and interpatient variability, to a specific therapeutic agent (2,3). This contrasts with the widely held clinical pharmacology dogma that interpatient variability in therapeutic response is principally due to variability in pharmacokinetic and pharmacologic processes. Presently, however, the relative contributions of each of these variabilities to the ultimate therapeutic response are typically unclear, most significantly due to limited availability of relevant data and methods and are likely to vary from one therapeutic class to another. Thus, the systems therapeutics framework suggests important future research needs in accounting for both processes and their independent variabilities. It is noted that some of the overall variability in conventional PK-PD modeling is likely to be due to variability in disease processes in addition to PK variability. 

Conclusions – It is our hope that the systems therapeutics framework will help stimulate research 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 on the other. Based on its two parallel processes and systems components, this framework has provided a more holistic view of the interfaces between pharmacology, pathophysiology and medicine than the commonly used single linear pharmacotherapeutics process. The inclusion of initiators or drivers for both processes provides potential new model-based approaches in clinical pharmacology and therapeutics. We further 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 and variability.

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. Therapeutics Research Institute. Systems Therapeutics: Diagram, Definitions and Illustrative Examples, TRI-institute.org, April 2018 (last edited August 2021).
3. Therapeutics Research Institute. Systems Therapeutics Framework: Development and Structure, TRI-institute.org, August 2021. 
4. Rowland M, Tozer TN (2011). Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, Fourth edition, Lippincott Williams & Wilkins, Philadelphia (Chapter 12, Variability, pp. 333-356).
5. 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.
6. Therapeutics Research Institute. Systems Therapeutics: Variabilities, TRI-institute.org, May 2016. 
7. Barabasi AL, Gulbahce N, Loscalzo J (2011). Network medicine: a network-based approach to human disease. Nat. Rev. Genetics, 12:56-68.
8. Silverman E, Harald H, Schmidt HW, Anastasiadou E, Altucci L, et al. Molecular networks in Network Medicine: Development and applications (2020). Wiley Interdisciplinary Reviews: Systems Biology and Medicine, vol. 12(6).
9. Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979). Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin. Pharmacol. Ther., 25:358-371.
10. Jusko WJ (1993). Conceptualization of drug distribution to a hypothetical pharmacodynamic effect compartment. Clin. Pharmacol. Ther., 54:112-113

Glossary

Below is a glossary of the individual systems components for the pharmacologic and pathophysiologic processes represented in the systems therapeutics diagram presented above. Examples for each systems component are from among approved treatments and diseases that have previously been addressed in individual posts on the Therapeutics Research Institute’s website, TRI-institute.org.  

Pharmacologic Processes

Pharmacologic Agent 

A compound, e.g., a small molecule or a large biopharmaceutical, that initiates the pharmacologic process by interacting with a pharmacologic response element. 

Examples:

• esomeprazole (Nexium)
• sildenafil (Viagra)

Pharmacologic Response Element

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

Examples:

• H+/K+ ATPase (proton pump)
• cGMP-specific phosphodiesterase type 5 (PDE5)

Pharmacologic Mechanism

Molecular mechanism of action, typically involving a molecular pathway resulting in a biochemical reaction (via signal transduction). 

Examples:

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

Pharmacologic Response

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

Examples:

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

Clinical Effect

A pharmacologic effect at the clinical level, which represents the pharmacologic basis for a therapeutic response (via translation). 

Examples:

• Decreased symptoms from gastric acidity (by proton pump inhibitor)
• 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.

Examples:

• Currently not known 

Etiologic Causative Factor

A genetic or non-genetic factor, upon interaction with an intrinsic operator (via disease preindication), determines a disease specific progression. 

Examples:

• Dihydrotestosterone (DHT)-induced growth factors and their receptors (in Benign Prostatic Hyperplasia)
• 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 from etiologic causative factor (via disease initiation). 

Examples:

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

Pathophysiologic Process

Ongoing pathophysiologic process (via pathogenesis), possibly both structural and functional.

Examples:

• Formation of discrete hyperplastic nodules in periurethral region (in Benign Prostatic Hyperplasia)
• 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 (via progression), typically independent of a specific etiologic causative factor. 

Examples:

• Lower urinary tract symptoms (in Benign Prostatic Hyperplasia)
• Loss of bone mineral density and risk of 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.

Examples:

• Symptom relief and mucosal healing (e.g., after proton pump inhibitors in Acid Reflux and Ulcer Disease)
• Improved erection (e.g., after PDE5 inhibitors in Male Erectile Dysfunction)
• Decreased urinary frequency (e.g., after 5-alpha reductase inhibitors in Benign Prostatic Hyperplasia)
• Decreased bone fractures (e.g., after bisphosphonates in Osteoporosis)