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.