Category Archives: Systems Therapeutics

Systems Therapeutics project

SYSTEMS THERAPEUTICS

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

Synopsis

Introduction

Systems Therapeutics Diagram

Systems Therapeutics Categories

Illustrative Examples

Discussion

References

Glossary

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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.

Figure 1. Systems Therapeutics Diagram

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

Category II – at the Cellular Level: Mechanisms/Pathways

Category III – at the Tissue/Organ Level: Responses/Processes

Category IV – at the 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 – 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)

Pharmacologic Mechanism: Regulator of Cystic Fibrosis Transmembrane Conductance (CFTR)

Indication: Cystic Fibrosis

Figure 2. Illustrative Example for Category I

Illustrative Example for Systems Therapeutics Category II (Figure 3)

Pharmacologic Mechanism: Inhibition of HMG-CoA Reductase

Indication: Hypercholesterolemia

Figure 3. Illustrative Example for Category II

Illustrative Example for Systems Therapeutics Category III (Figure 4)

Pharmacologic Mechanism: Inhibition of Angiotensin-Converting Enzyme (ACE)

Indication: Hypertension (and other cardiovascular indications)

Figure 4. Illustrative Example for Category III

Illustrative Example for Systems Therapeutics Category IV (Figure 5)

Pharmacologic Mechanism: Inhibition of Cyclooxygenase (COX-1/COX-2)

Indication: Osteoarthritis (and other indications)

Figure 5. Illustrative Example for Category IV

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)

Systems Therapeutics Framework: Development and Structure

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 in the 1992 edition of Oxford Textbook of Clinical Pharmacology and Drug Therapy (1), which describes the chain of events linking the pharmacologic effects of drugs to their clinical therapeutic response, and includes several examples. For reference, a commonly used generic diagram is shown below illustrating the sequence of events (shown vertically) from a drug dose, through concentration and pharmacologic effect, to therapeutic response.  

Efforts on a systems therapeutics diagram were initiated in the mid 2010’s, although it was not initially clear how this work would evolve. The objective was to create a systems therapeutics framework, depicting the pharmacologic and pathophysiologic processes separately (shown horizontally), each with a set of systems components at different biologic levels, thus enabling the presentation of interactions between these two processes at the different biologic levels. 

Development of a Systems Therapeutics Framework

The development of the systems therapeutics framework was very much an iterative process, e.g., determining the number and naming of the systems components representing the different biological levels, and their connections and interactions. Five different iterations of a systems therapeutics diagram were subsequently developed and posted on the Therapeutics Research Institute’s website, tri-institute.org, between 2015 and 2018. This involved an evolving construction of a systems therapeutics diagram, four systems therapeutics categories, relevant definitions, and illustrative examples of the different categories, as well as a discussion of variabilities in the pharmacologic and pathophysiologic processes. 

During this development period there were important clarifications both at the front end of the diagram, i.e., the drivers of these two processes, pharmacologic agent and intrinsic operator, for the pharmacologic and pathophysiologic processes, respectively, and at the back end, i.e., net therapeutic response, which represents where the clinical (pharmacologic) effect and disease manifestation interact; thus, a symmetry between these processes was achieved. Importantly, this framework shows the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a single linear diagram (see diagram above), and thus illustrating for a given pharmacologic agent at what biologic level the pharmacologic and pathophysiologic processes interact to result in a therapeutic response. There was also an ongoing effort on the nomenclature, definitions and examples; these are all provided in Systems Therapeutics: Diagram, Definition and Illustrative Examples, Therapeutics Research Institute’s website (2).

Systems Therapeutics Diagram

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

The organizing principle underlying the systems therapeutics diagram involves 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, in addition to the initiating entities or drivers of these processes, and the ultimate therapeutic response. 

The systems components for pharmacologic processes involve a pharmacologic response element, followed by a pharmacologic mechanism, a pharmacologic response, and a clinical effect, whereas the systems components for pathophysiologic processes involve 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).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 process side, a pharmacologic agent (a drug), interacting with a pharmacologic response element (a receptor or so-called drug target), and its concentration or exposure, is the fundamental driver of pharmacologic processes. On the pathophysiologic process side, a hypothetical intrinsic operator is proposed as an initiator interacting with and influencing an etiologic causative factor, and serving as a driver of pathophysiologic processes. This hypothetical intrinsic operator is intended to cover biologic entities identified using advanced network-based approaches in disease initiation.

The culminating result of the interaction between these two processes, independent of the biologic level of the pivotal interaction, involves a clinical therapeutic response, determined by the clinical (pharmacologic) effect and disease manifestation. While it is well recognized that there is a wide variability in the clinical therapeutic response of individual patients to a given approved drug, 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 interpatient 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. 

Systems Therapeutics Categories

The systems therapeutics diagram 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

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, genes) or genome-based therapies (interference with altered gene products).

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 of Metabolism-based Therapy – These can involve metabolism-based therapies (interference with a biochemical mechanism or a disease network-linked pathway).

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 of Function-based Therapy – These can involve function-based therapies (modulation of a (normal) physiologic function or activity).

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 of Symptom-based Therapy – These can involve symptom-based therapies (various symptomatic or palliative treatments).

Examples, Definitions, and Glossary

In addition to descriptions of the systems therapeutics framework and diagram, examples of approved drugs for each of the systems therapeutics categories were provided in Systems Therapeutics: Diagram, Definitions and Illustrative Examples, which was posted on the Therapeutics Research Institute’s website (2). Furthermore, this post also contains illustrative examples for the different systems therapeutics categories of how the pivotal interaction occurs between the two processes. Finally, this post also contains definitions and a glossary of the individual systems components for the pharmacologic and pathophysiologic processes represented in the systems therapeutics diagram.

Discussion

The systems therapeutics diagram and framework presented here represents the culmination of years long effort on the pharmacotherapeutics process. Of note are the two initiators or drivers of these two processes, one actual (pharmacologic agent), the other hypothetical (intrinsic operator); the four systems components for each of the pharmacologic and pathophysiologic processes and their interactions to create four different systems therapeutic categories; and the final common therapeutic response from the two end events of the pharmacologic and pathophysiologic processes, clinical effect and disease manifestation. 

It is worth highlighting a few aspects of the systems therapeutics framework and contrast these to the “classic” single linear diagram from a dose of a drug to pharmacologic effect or therapeutic response:

  • They differ in structure: The systems therapeutics framework involves two parallel processes, pharmacologic and pathophysiologic, each showing four biologic levels of potential interactions, at the molecular, cellular, tissue/organ and clinical levels, initiated by their respective drivers and culminating in a therapeutic response, in contrast to the single linear model from drug dose and exposure through pharmacologic actions, e.g., molecular, cellular, tissue/organ or clinical levels, resulting in pharmacologic effect or therapeutic response.
  • They differ in suggestive causes of variabilities in therapeutic response: The systems therapeutics framework recognizes the potential for interindividual variability not only on the pharmacologic process side, e.g., due to exposure or pharmacologic receptor differences, but also on the pathophysiologic side, e.g., due to differences in pathogenic pathways or disease manifestations, whereas the single linear sequence model views drug exposure as the key determinant of variability in pharmacologic effect or therapeutic response. Thus, the systems therapeutics framework views variabilities in both processes as contributors and co-determinants of variability in therapeutic response, although at the present time it may be difficult to determine pathophysiologic process variability and the respective contributions of both processes.
  • They differ in their abilities to illustrate how the pharmacologic and pathophysiologic process components interact: The systems therapeutics framework allows for a mechanistic explanation how the two processes interact, depending on the biologic level of the pivotal interaction. This has been illustrated by examples for each of the four levels of interactions, i.e., systems therapeutics categories, how the pharmacologic and pathophysiologic processes interact to produce a therapeutic response. There is not an equivalent manner to illustrate these interactions in the single linear sequence model.  
  • They differ in their focus on the initiators or drivers of their respective processes: The systems therapeutics framework allows for initiators or drivers of both processes. On the pharmacologic process side, the fundamental driver of the pharmacologic processes obviously is the pharmacologic agent in question and its exposure, whereas, on the pathophysiologic process side, a hypothetical intrinsic operator is proposed as an initiator interacting with and influencing an etiologic factor, and thus serving as a driver of the pathophysiologic processes. While currently there are no known examples of such initiators or drivers, current work in advanced network-based approaches in disease initiation suggests the existence of a driver mechanism. There is not an equivalent manner to suggest a disease process driver in the single linear sequence model.

Considering the above highlights, the systems therapeutics framework suggests future research needs, such as to address disease process measurements and variability, and to further define disease process initiators and drivers. It is noted that the some of the overall variability in conventional PK-PD modeling is likely to be due to variability in disease processes.

It is hoped that the systems therapeutics framework advanced here will help stimulate research towards 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: Oxford Textbook of Clinical Pharmacology and Drug Therapy, Oxford University Press, Oxford, 1992 (Chapter 5. The Therapeutic Process, pp. 55-66).
  2. Bjornsson, TD: Systems Therapeutics: Diagram, Definitions and Illustrative Examples. Therapeutics Research Institute’s website, tri-institute.org, April 2018, last edited August 5, 2021.

 

Systems Therapeutics: Diagram, Definitions and Illustrative Examples

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. Both of these processes have their own sets of initiators or drivers. These different levels of interactions then determine four different systems therapeutics categories. Illustrative examples of these four different systems therapeutics categories are provided, as well as a glossary of the systems components. The systems therapeutics diagram further suggests that the wide interpatient variability in therapeutic response characteristics to approved drugs is contributed to by variabilities in both of these two processes. It is hoped that the systems therapeutics framework advanced here will promote discussions regarding the need for better understanding of the determinants of therapeutic response characteristics of modern therapeutics. 

Contents:

  • Executive Summary
  • Introduction
  • Systems Therapeutics Diagram
  • Systems Therapeutics Categories
  • Systems Therapeutics Illustrative Examples
  • 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 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 provide an updated summary of a systems therapeutics framework, depicting pharmacologic and pathophysiologic processes separately, thus enabling the presentation of the different biologic levels of interactions between these two processes. This paper summarizes and updates five previous iterations on the systems therapeutics framework posted on the Therapeutics Research Institute’s website, TRI-institute.org, between April 2015 and February 2018. During this period, this has included an evolving construction of a systems therapeutics diagram, four systems therapeutics categories, relevant definitions, and illustrative examples of the different categories, as well as a discussion of variabilities in pharmacologic and pathophysiologic processes.

Systems Therapeutics Diagram

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

The organizing principle underlying the systems therapeutics diagram presented above involves 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, 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 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). Brief descriptions of the individual systems therapeutics components are provided in the glossary below, including examples for each component.

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 process side, a pharmacologic agent (a drug), interacting with a pharmacologic response element (e.g., a receptor or so-called drug target), and its concentration or exposure, is the fundamental driver of pharmacologic processes. On the pathophysiologic process side, a hypothetical intrinsic operator is proposed as an initiating entity or driver 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 identified using advanced bioinformatics and network-based approaches in disease initiation.

The culminating result of the interaction between these two processes, independent of the biologic level of the pivotal interaction, involves a clinical therapeutic response, determined by the clinical (pharmacologic) effect and the disease manifestation. 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 of these two processes, pharmacologic and pathophysiologic, have their inherent variabilities. This systems therapeutics construct thus further suggests that interpatient 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 relevant data and methods, and are likely to vary from one therapeutic class to another. A general commentary (6) discussed variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression).

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 response element and the etiologic causative factor, respectively.

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

  • 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 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., Lipitor (atorvastatin) for Hypercholesterolemia
  • TNF-a Inhibitors, e.g., Humira (adalimumab) for Rheumatoid Arthritis
  • Proton Pump Inhibitors, e.g., Nexium (esomeprazole) for Gastric Reflux & Ulcer Disease

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

  • Angiotensin II Blockers, e.g., Avapro (irbesartan) for Hypertension
  • PDE-5 Inhibitors, e.g., Cialis (tadalafil) for Male Erectile Dysfunction
  • 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 of Symptom-based Therapy – These can involve symptom-based therapies (various symptomatic or palliative treatments):

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

Systems Therapeutics Illustrative Examples

Below are illustrative examples for each of the four systems therapeutics categories. The charts follows the design of the systems therapeutics diagram discussed above. 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 Category I:

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator for Cystic Fibrosis.
See diagram below; click for a larger diagram.

Illustrative Example for Category II:

Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD)
See diagram below; click for a larger diagram.

Illustrative Example for Category III:

Angiotensin-Converting Enzyme (ACE) Inhibitors for Hypertension
See diagram below; click for a larger diagram.

Illustrative Example for Category IV:

Non-Steroidal Anti-inflammatory Agents (NSAIDs) for Osteoarthritis
See diagram below; click for a larger diagram.

Discussion

The systems therapeutics diagram has been constructed with the goal of serving to facilitate better 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 and pathophysiologic processes interact to result in a therapeutic response. The illustrative examples presented for the four different systems therapeutics categories offer descriptions of the two progressing processes in a storyboard-like fashion, highlighting at what biology level the pivotal interaction occurs between these two 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). The former driver is well recognized, including its concentration or exposure, while the 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 (6,7). Also, one can speculate that the wide range in the age of disease onset for different diseases, from first year of life to late in life, does suggest unrecognized driving factors acting on an etiologic causative factor. At the present time, however, we are not aware of any current pharmacologic agent/mechanism interacting with such a hypothetical intrinsic operator (which when identified could be represented as systems therapeutics Category Zero). 

It is our hope that the systems therapeutics framework advanced here 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 of modern therapeutics on the other. It has previously been noted that although this systems-based framework does not explicitly address interpatient variability in therapeutic response, this framework clearly suggests that variabilities in pharmacologic processes and pathophysiologic processes both contribute to the overall variability in therapeutic response. 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.

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. 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, May 2016. https://tri-institute.org/TyQij
  7. Barabasi AL, Gulbahce N, Loscalzo J (2011). Network medicine: a network-based approach to human disease. Nat. Rev. Genetics, 12:56-68

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, 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 (proton pump); and
   cGMP-specific phosphodiesterase type 5 (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 represents the pharmacologic basis for a therapeutic response (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.

Examples:
   Currently typically not known 

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); 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 Benign Prostatic Hyperplasia); 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 Benign Prostatic Hyperplasia); 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 Benign Prostatic Hyperplasia); and
   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 nhibitors 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)

Systems Therapeutics: Representative Illustrative Example for Category II

Introduction

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed (1), 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 the clinical level, culminating in a therapeutic response. The interactions at these different biologic levels then determine the four different systems therapeutics categories, Categories I – IV. The above referenced summary only named therapeutic class examples for each of the four systems therapeutics categories, but did not include representative illustrative examples for each of these categories.

The purpose of this post is to provide an illustrative example for one of the systems therapeutics categories, Category II, where the pivotal interaction between the pharmacologic and pathophysiologic processes involves a fundamental biochemical mechanism at the cellular level, related to the disease evolution, although not necessarily an etiologic pathway. The illustrative example chosen for Category II involves Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD). Future communications will provide illustrative examples for the other systems therapeutics categories.

Illustrative Example for Category II

The chart below (click for a larger view) illustrates the individual systems components for pharmacologic and pathophysiologic processes for Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD), culminating in a therapeutic response.

This chart follows the design of the systems therapeutics diagram previously referenced (1), which includes definitions of the individual systems therapeutics categories and a glossary of the individual systems components. The chart was developed using OmniGraffle (The Omni Group, Seattle, WA). The bold connection between pharmacologic and pathophysiologic processes represents the pivotal interaction between these processes, which here is at the cellular level (Category II). 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.

Comments

The systems therapeutics framework referenced above (1), including a diagram, four categories, definitions and a glossary, was constructed with the goal of serving to facilitate discussion and understanding of the different types of FDA approved drugs. Importantly, this framework attempts to illustrate the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a singular pharmacotherapeutic process, in contrast to previously published attempts, thus enabling highlighting at what level the pharmacologic process engages with the pathophysiologic process. It has previously been noted that this systems-based framework does not explicitly address interpatient variability in therapeutic response, although this framework clearly suggests that variabilities in pharmacologic processes and pathophysiologic processes both contribute to the overall variability in therapeutic response. A general commentary on variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression) has been previously published (2).

The chart presented in this publication has provided a representative illustrative example for one of the four systems therapeutics categories (Category II). It is hoped that this illustration will serve as a useful example of how the systems therapeutics framework can provide a framework for facilitating discussions concerning various aspects of different therapeutics, as well as suggesting areas in need of future research and better understanding.

References

  1. Systems Therapeutics: Where Pharmacologic and Pathophysiologic Processes Interact. Therapeutics Research Institute, February 2017.
    This post summarizes the systems therapeutics framework, including the systems therapeutics diagram, its four categories, related definitions, as well as a glossary. Note the example presented above for Category II was initially named as Category III.
  2. Systems Therapeutics: Variabilities. Therapeutics Research Institute, May 2016. 
    This post discusses variability in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression). Note the systems therapeutics diagram in this post represents an earlier version of the diagram. 

 

 

 

 

Systems Therapeutics: Where Pharmacologic and Pathophysiologic Processes Interact

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.

Systems Therapeutics: Updated Diagram

Background

Two reports have been posted on Systems Therapeutics on this website, first, “Systems Therapeutics: A Diagram and Four Categories” in April 2015 (1), and second, “Systems Therapeutics: Variabilities” in May 2016 (2). The purpose of the underlying systems therapeutics diagram is to provide a high-level framework to facilitate discussions on how pharmacologic processes and pathophysiologic processes interact to produce a therapeutic response.

In essence, the systems therapeutics diagram consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, each starting at the molecular level, through the cellular and tissue/organ levels, and finally the clinical level, culminating in therapeutic response. The pivotal interactions between the pharmacologic and pathophysiologic processes, at each of the four biologic levels, 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 was outlined in the May 2015 post. In addition, each of these two processes, pharmacologic and pathophysiologic processes, have their inherent variabilities, as was outlined in the May 2016 post, which also suggested that variability on the pathophysiologic process side might be an important determinant of patient therapeutic response characteristics, including response variability and responder rate, in addition to variability on the pharmacologic process side, although it is unclear where the source of such variability might reside, including potentially at different levels.

Updated Diagram

The current report presents an updated systems therapeutics diagram, see below (click here for a larger graph), that includes the following modifications of the diagram presented in the May 2016 post:

systems-therapeutics-sep-2016

  • On the pharmacologic processes side, the following systems components have changed names: “Pharmacologic Agent” has replaced “Drug” and “Drug Concentration”, and “Pharmacologic Response Element” has replaced “Pharmacologic Target”. The rationale is to use more neutral and descriptive terms, with an emphasis on an agent acting on an element in a pharmacologic pathway, resulting in a response. Here, the pharmacologic agent, and its concentration or exposure, is the undisputed fundamental driver of pharmacologic processes, including interpatient variability. Another change involves adding at the clinical level “Clinical Effect” as the last systems component on the pharmacologic processes side, corresponding to “Disease Manifestation” on the pathophysiologic processes side. The descriptors for the transitions from one systems component to another on the pharmacologic processes side, e., signal transduction, pharmacodynamics and translation, remain unchanged.
  • On the pathophysiologic processes side, the following systems components have changed names: “Intrinsic Operator” has replaced “Environmental” and “Factor”, and “Etiologic Causative Factor” has replaced “Etiologic Factor”. The main rationale is to simplify and depict similarly the initial events of both pharmacologic and pathophysiologic processes, with an emphasis on an etiologic factor in a disease network being driven by a hypothetical operator, eventually leading to manifestation of a disease. It is noted that this construct, incorporating a hypothetical systems component at the beginning of pathophysiologic processes, is intended in part to lump together different entities thought to influence “Etiologic Causative Factor” (as addressed in the May 2016 post, including etiome and network medicine), and in part to serve as a hypothetical driver of pathophysiologic processes, including interpatient variability. Whether this simple hypothesis survives the test of time is obviously unclear, but for now this “Intrinsic Operator” serves a role as an integral systems component. The descriptors for the transitions from one system component to another on the pathophysiologic process side, e., disease initiation, pathogenesis and progression, remain unchanged.

Comments

The systems therapeutics diagram, first introduced in the April 2015 post (1) has been modified twice, first in the May 2016 post (2), and now in the present report. Both modification have principally involved the system components at the beginning of the pharmacologic and pathophysiologic processes, how they are depicted and named.

This updated framework, highlighting how these parallel processes – pharmacologic and pathophysiologic – contribute to patient therapeutic response characteristics, also helps focus on areas where future basic research efforts are sorely needed, such as initiating disease process mechanisms and variability in disease process drivers.

It is our hope that those interested in this general subject will find the updated systems therapeutics diagram useful as an aid in thinking about the various determinants, known and unknown, of patient therapeutic response to approved drugs, while recognizing our limited understanding in this area at this time.

References

  1. Therapeutics Research Institute: Systems Therapeutics: A Diagram and Four Categories, May 2015. https://tri-institute.org/niDFW
  2. Therapeutics Research Institute: Systems Therapeutics: Variabilities, May 2016. https://tri-institute.org/TyQij

 

Systems Therapeutics: Variabilities

Introduction

A systems therapeutics framework, “Systems Therapeutics: A Diagram and Four Categories”, was recently presented on this website, tri-institute.org (2015), illustrating pharmacologic processes and pathophysiologic processes separately. This framework incorporated four different levels of interactions between these two fundamental processes, 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. This conceptual framework builds on previous work by others, principally Grahame-Smith & Aronson (1992) and Post et al. (2005), and significantly expands previous work by Bjornsson (1996). The purpose of this initial work on systems therapeutics was to present a theoretical framework, which could be useful when examining different types of therapeutic effects; definitions and a few examples were presented for each systems therapeutics category.

Fundamental to considerations of therapeutic effects is the issue of interpatient variabilities, and determinants or drivers of such variabilities where these are understood, as discussed by Rowland & Tozer (2011) and Eichler et al. (2011). Variability in pharmacologic processes for approved drugs, principally in pharmacokinetics and pharmacodynamics, have been well recognized and characterized over that past several decades, although the final step, the translation from pharmacologic response to therapeutic effect, still remains elusive in many instances, particularly in drug discovery and development. Interpatient variability in pathophysiologic processes, from disease initiation to disease manifestations or signs and symptoms, however, has received much less attention than that in pharmacologic processes. Thus, when addressing interpatient variability in therapeutic response to approved drugs, including response range, response magnitude, responder rate, and lack of response, it is not always obvious to what extent interpatient variability in pathophysiologic processes, or disease progression, might contribute to the observed therapeutic response, in addition to variability in pharmacologic processes.

Since issues of such variabilities were not addresses in the previous paper, and considering their importance, the purpose of the present paper is to highlight key areas in systems therapeutics variabilities. Below is a graph of the systems therapeutics framework, illustrating the pharmacologic processes and pathophysiologic processes separately (click for a larger graph).

Systems Therapeutics graph

Variability in Pharmacologic Processes (Pharmacokinetics and Pharmacodynamics)

For the past three to four decades it has been assumed that interpatient variability in therapeutic effect is determined by individual differences in pharmacokinetics, pharmacodynamics and compliance. Note that the net effect of pharmacokinetics and compliance, the drug and its concentration at the site of action, as illustrated in the top left hand corner of the graph, can be considered as the initial determinant or driver of pharmacologic processes.

Variability is pharmacokinetics (PK), which covers drug absorption, distribution, drug metabolism and drug elimination, has been amply demonstrated. Tables of pharmacokinetic parameters of approved drugs are widely available and accessible, e.g., in textbooks and reviews of individual drugs or pharmacologic classes. A comprehensive table of pharmacokinetic parameters of approved drugs is included as an appendix by Thummel et al. (2011) in Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. This table lists for each drug its bioavailability, urinary excretion, plasma protein binding, clearance, volume of distribution, elimination half-life, peak time and peak concentration, typically expressed as mean ± standard deviation, but sometimes as mean and range in values. A coefficient of variation (CV) for clearance, one estimate of interpatient variation, of approx. 30% is common, but these can range considerably; obviously, the range in values can be significantly larger. A recent paper by Gao et al. (2011) on over 15 targeted anticancer drugs illustrates their wide pharmacokinetic variability, showing CV for exposure varying between approx. 25-82%, and trough levels varying between approx. 6-26 fold.

Variability in pharmacodynamics (PD), covering the relationship between drug concentration and pharmacological response intensity, has received less attention than that in pharmacokinetics. While there was an earlier belief that pharmacokinetic differences and compliance were more important as determinants of pharmacologic response than pharmacodynamic differences, it has become accepted that pharmacodynamic variability is at least as wide as pharmacokinetic variability, sometimes exceeding one order of magnitude, for early reviews see Levy et al. (1994) and Levy (1998). Commonly used examples of variation in pharmacologic response in the earlier literature involved various physiological, biochemical or related measures, e.g., pain relief and sedation, cardiovascular, anticoagulant, and metabolic measures. As a specific example, pharmacokinetic-pharmacodynamic modeling of the opioid analgesics fentanyl, alfentanil and trefentanil by Lemmens et al. (1994; cited in Levy 1998), using EEG as a pharmacodynamic measure, reported a range in CV for EC50 (drug concentration producing 50% of Emax, i.e., the maximum effect) of 47 to 85%. Interpatient variability in pharmacodynamics can be manifested in the different parameters of the concentration vs. response relationship, i.e., EC50, Emax, slope parameter of the sigmoid curve, and baseline; numerous factors may impact these.

Variability in Pathophysiologic Processes (Disease Initiation and Disease Progression)

While detailed descriptions of etiology, pathogenesis, pathophysiology, pathology, prognosis, and clinical manifestations and treatment of diseases are provided in textbooks of pathology and medicine, there is limited discussion of quantitative patient variability in disease progression over time. Ideally, such information would come from longitudinal studies on the natural history of diseases, but unfortunately, these are not available for most diseases, although clinically, such variability has been well recognized for centuries.

Disease pathophysiologic processes can be visualized as starting with disease initiation (refer to the bottom left hand corner of the graph). Recent work using advanced bioinformatics and network-based approaches has started to elucidate some of the components of disease initiation and their interactions. Although such work has not been directly aimed at variability, because of its promise in the future, two examples are included. First, Liu et al. (2009) introduced the term “etiome” to describe the combination of genetic and non-genetic etiologic factors associated with diseases; this publication identified 863 diseases as having both etiologic genetic and environmental factors (the latter referring to non-genetic factors in the broadest sense). Second, work by Barabasi et al. (2011) and others on so-called network medicine has sought to explore systematically the molecular connections and complexity of individual diseases and the molecular relationships among different (patho)phenotypes. The exciting promise of such approaches includes how these network constructs may connect with pathophysiologic processes or disease progression – systems pathobiology and clinical phenotypes – and thus contribute to determinants or drivers of individual patient’s disease progression; see opinion paper by Loscalzo & Barabasi (2011).

As was mentioned above, there are only limited examples of the natural history of diseases or disease progression. However, data on disease progression over relatively short periods of time, involving repeated measures of disease status, are available and have been collected as part of clinical trials of drug efficacy, as part of control or placebo groups, and as analyzed by disease progress models using pharmacostatistical techniques. Note some assumptions may need to be made regarding the use of placebo groups as representative of natural history of disease. Several different disease progress models have been described, depending on the nature of the disease in question, including symptomatic and disease-modifying effects, and continuous or discontinuous progression, see for example Holford et al. (2012). Such pharmacometrics models have been developed for several diseases, e.g., Alzheimer’s disease, Parkinson’s disease, type-2 diabetes, depression, schizophrenia, chronic obstructive pulmonary disease, and osteoporosis; see summaries by Holford (2013). One example of disease progression involves assessment of cognitive deterioration in Alzheimer’s disease by Ito et al. (2011), based on ADIS-cog measurements, which showed significant variability, with age, gender, APOEe4 genotype and baseline status determining the decline in cognition. Studies on Parkinson’s disease have shown marked variability among patients on the rate of progression, assessed with global functional score, see Holford & Nutt (2008), suggesting there are distinct disease subtypes with different rates of progression.

Comments

Considering the significant interpatient variability in therapeutic response to approved drugs, including responder rate and response range, it is important to understand what processes contribute to such variability and their approximate contributions. This paper looked at three key areas, i.e., pharmacokinetic and pharmacodynamic variabilities in pharmacologic processes and disease progression in pathophysiologic processes; in addition, there was a brief introduction to bioinformatics efforts on disease initiation. Key comments are as follows:

  • There are well documented significant interpatient pharmacokinetic and pharmacodynamic differences; there are indications that the latter may be at least as wide as the former.
  • As expected, it is noted that reporting of PK parameters is better standardized than that of PD parameters. It is desirable that more uniform approaches are used in the reporting of PK and PD data and parameters, including the reporting of range in values.
  • It is recommended that the control or placebo data from disease progress models be routinely reported as an estimate of disease progression variability, including any caveats regarding placebo response.
  • It was noted during the preparation of this report that there are relatively few good up-to-date summaries/reviews on variabilities within these three key processes, particularly pharmacodynamics and disease progression.
  • Knowledge of variabilities in key underlying processes will provide better understanding of therapeutic response characteristics of approved drugs.
  • One looks forward to the time when bioinformatics approaches to disease initiation can be linked to pharmacometrics approaches to disease progression.

References

  • Barabasi AL, Gulbahce N, Loscalzo J (2011). Network medicine: a network-based approach to human disease. Nat. Rev. Genetics, 12:56-68.
  • Bjornsson TD (1996). A classification of drug action based on therapeutic effects. J. Clin. Pharmacol., 36:669-673 (p. 670, Fig. !).
  •  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.
  • Gao B, Yeap S, Clementis A, Balakrishnar B, Wong M, Gurney H (2012). Evidence for therapeutic drug monitoring of targeted anticancer therapies. J. Clin. Oncol., 30:4017-4025.
  • 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, Fig. 5.1).
  • Holford N, Nutt JG (2008). Disease progression, drug action and Parkinson’s disease: Why time cannot be ignored. Eur. J. Clin. Pharmacol., 64:207-216.
  • Holford NHG, Mould DR, Peck CC (2012). Disease progress models. In: Principles of Clinical Pharmacology, Adkinson AJ, Huang SM, Lertora JJL, Markey SP, editors, Third edition, Academic Press, New York, pp. 369-382.
  • Holford N (2013). Clinical pharmacology = disease progression + drug action. Br. J. Clin. Pharmacol., 79:18-27.
  • Ito K, Corrigan B, Zhao Q, French J, Miller R, Soares H, Katz E, Nicholas T, Billing B, Anziano R, Fullerton T (2011). Disease progression model for cognitive deterioration from Alzheimer’s Disease Neuroimaging Initiative database. Alzheimer’s & Dementia, 7:151-160.
  • Lemmens HJM, Dyck JB, Shafer SL, Stanski DR (1994). Pharmacokinetic-pharmacodynamic modeling in drug development: application to the investigational opioid trefentanil. Clin. Pharmacol. Ther., 56:261-271 (p. 270, Table VI).
  • Levy G, Ebling WF, Forrest A (1994). Concentration- or effect-controlled clinical trials with sparse data. Clin. Pharmacol. Ther., 56:1-8 (p.2, Table 1).
  • Levy G (1998). Predicting effective drug concentrations for individual patients. Clin. Pharmacokinet., 34:323-333.
  • Liu YI, Wise PH, Butte AJ (2009). The “etiome”: identification and clustering of human disease etiologic factors. BMC Bioinformatics, 10 (Suppl. 2):S14, 1-10.
  • Loscalzo J, Barabasi AL (2011). Systems biology and the future of medicine. Wiley Interdiscip. Rev. Syst. Biol. Med., 3:619-627.
  • Post TM, Freijer JI, DeJongh J, and Danhof M (2005). Disease system analysis: Basic disease progression models in degenerative disease. Pharm. Res., 22:1038-1049 (p. 1039, Fig. 1).
  • Rowland M, Tozer TN (2011). Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, Fourth edition, Lippincott Williams & Wilkins, Philadelphia (Chapter 12, Variability, pp. 333-356).
  • Thummel KE, Shen DD, Isoherranen N (2011). Design and optimization of dosage regimens: Pharmacokinetic data. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics,  Brunton, L, Chabner B, Knollman, B, editors, Twelfth edition, McGraw Hill, New York, p. 1891.
  • Therapeutics Research Institute (2015). Systems Therapeutics: A Diagram and Four Categories, April, 2015. tri-institute.org/niDFW.

Systems Therapeutics: A Diagram and Four Categories

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 Framework.graffle - 1

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)