Pharmacometrics
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Pharmacometrics is a field of study of the methodology and application of models for
disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
and
pharmacological Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
measurement Measurement is the quantification of attributes of an object or event, which can be used to compare with other objects or events. In other words, measurement is a process of determining how large or small a physical quantity is as compared ...
. It uses mathematical models of
biology Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary i ...
, pharmacology, disease, and
physiology Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
to describe and quantify interactions between
xenobiotics A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
and patients (human and non-human), including beneficial effects and adverse effects. It is normally applied to quantify drug, disease and trial information to aid efficient drug development, regulatory decisions and rational drug treatment in patients. Pharmacometrics uses models based on pharmacology, physiology, and disease for quantitative analysis of interactions between drugs and patients. This involves Systems pharmacology,
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
,
pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...
and disease progression with a focus on
populations Population typically refers to the number of people in a single area, whether it be a city or town, region, country, continent, or the world. Governments typically quantify the size of the resident population within their jurisdiction using a ...
and variability. Mould and Upton provide an overview of basic concepts in population modeling, simulation, and model-based drug development. A major focus of pharmacometrics is to understand variability in drug response. Variability may be predictable (e.g. due to differences in body weight or kidney function) or apparently unpredictable (a reflection of the current lack of knowledge).


Origins

The term "pharmacometrics" first appeared in literature in the preface of the 1964 book "Evaluation of Drug Activities: Pharmacometrics":
The sub-title of the book is, as far as we are aware, a
neologism A neologism Greek νέο- ''néo''(="new") and λόγος /''lógos'' meaning "speech, utterance"] is a relatively recent or isolated term, word, or phrase that may be in the process of entering common use, but that has not been fully accepted int ...
, coined by one of us (A.L.B.), and the word is defined by the main title of the book, which could have been even more explicitly, if more verbosely, expressed as "The Identification and the Comparative Evaluation, Qualitative and Quantitative, of Drug Activities". The term has an etymological precedent in the now widely accepted "
Econometrics Econometrics is the application of Statistics, statistical methods to economic data in order to give Empirical evidence, empirical content to economic relationships.M. Hashem Pesaran (1987). "Econometrics," ''The New Palgrave: A Dictionary of ...
". We hope it will prove useful for distinguishing the kind of measurement discussed and described in this book from what is nowadays called
bioassay A bioassay is an analytical method to determine the concentration or potency of a substance by its effect on living animals or plants (''in vivo''), or on living cells or tissues(''in vitro''). A bioassay can be either quantal or quantitative, dir ...
; although the same techniques sometimes serve for both, their objectives are not at all identical.
However, the editors later state at the end of the preface:
...we have learned with interest and humility that Dr. Karl Beyer, a Vice-President of Merck, Sharpe and Dohme, Rahway, New Jersey, U.S.A., and current President of the American Pharmacological Society, "coined the word (Pharmacometrics) in the early '50s and has been using it in internal reports ever since" (J. R. Vane, personal communication). Moreover, one of the laboratories in the pharmacological department of his Company is "labeled 'Pharmacometrics'"! We do not know in exactly what sense Dr. Beyer has been using the word, though we find it difficult to think of any other legitimate one than that advanced above. We can only hope that he also thinks so and that its use in the title of this book may help to give it the wider currency that we believe it to deserve and all the "priority" rights to Dr. Beyer.


Types of models


Pharmacokinetics (PK)

Models of pharmacokinetic processes.


Pharmacodynamics (PD)

Models of
pharmacodynamic Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for ...
processes.


Physiologically based Pharmacokinetics

Physiologically based pharmacokinetic models


Exposure-response

Exposure-response models describe the relationship between exposure (or
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
), and response (or
pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...
) for both desired and undesired effects. See also dose-response.


Disease progression

The natural time course of a disease is often dynamic, with the tendency to become worse without treatment. Disease progression models are mainly used to understand the relationship between treatment, biomarker changes and clinical outcomes. These models describe the disease trajectory, by observing the change in the biomarker level, or the other clinically relevant endpoint that reflects the disease status, over time. There are three key classes of disease progression models:
empirical Empirical evidence for a proposition is evidence, i.e. what supports or counters this proposition, that is constituted by or accessible to sense experience or experimental procedure. Empirical evidence is of central importance to the sciences and ...
, semi-mechanistic, and systems biology. Most of the disease progression models are empirical, describing disease trajectory rather than the physiological background of the disease. The simplest model that is used to describe disease progression is a
linear model In statistics, the term linear model is used in different ways according to the context. The most common occurrence is in connection with regression models and the term is often taken as synonymous with linear regression model. However, the term ...
when the change of disease status over time is assumed to be constant.


Trial

Trial models describe variations from the nominal trial protocol due to things such as patient dropout and lack of adherence to the dosing regimen.


Organizations

Historically, pharmacometrics has been represented in related clinical pharmacology and statistics organizations. A number of smaller local organizations in Europe, United States, and New Zealand/Australia held local meetings. In the early 1990s, The PAGE meeting was organized and has been held yearly since then, although no official organization was present. Ette and Williams have provided a historical context from which the evolution of pharmacometrics can be appreciated. In 2011, the American Society of Pharmacometrics (ASoP) was founded by a number of local American groups, and over 600 members worldwide joined ASoP within 6 months. In 2012, ASoP evolved to the International Society of Pharmacometrics (ISoP) to reflect the increasing number of international members. ISoP's growth continues and the Society currently represents over 1000 members from almost 30 countries around the world. Regional groups include PAGE in Europe and PAGANZ in Australia and New Zealand. Pharmacometricians typically come from disciplines such as
Pharmacy Pharmacy is the science and practice of discovering, producing, preparing, dispensing, reviewing and monitoring medications, aiming to ensure the safe, effective, and affordable use of medicines. It is a miscellaneous science as it links heal ...
,
Clinical pharmacology Clinical pharmacology has been defined as "that discipline that teaches, does research, frames policy, gives information and advice about the actions and proper uses of medicines in humans and implements that knowledge in clinical practice". Clinic ...
,
Statistics Statistics (from German language, German: ''wikt:Statistik#German, Statistik'', "description of a State (polity), state, a country") is the discipline that concerns the collection, organization, analysis, interpretation, and presentation of ...
,
Medicine Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pract ...
, or
Engineering Engineering is the use of scientific method, scientific principles to design and build machines, structures, and other items, including bridges, tunnels, roads, vehicles, and buildings. The discipline of engineering encompasses a broad rang ...
. The first professor of pharmacometrics was Mats Karlsson,
Uppsala University Uppsala University ( sv, Uppsala universitet) is a public university, public research university in Uppsala, Sweden. Founded in 1477, it is the List of universities in Sweden, oldest university in Sweden and the Nordic countries still in opera ...
.


Journals

The main journals that publish work in pharmacometrics are: * AAPS J * CPT: PSP * CPT * J PKPD


References

{{reflist Pharmaceutical industry Pharmacodynamics Pharmacokinetics