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 adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...
and
pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...
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 to ...
. It uses mathematical models of
biology Biology is the scientific study of life and living organisms. It is a broad natural science that encompasses a wide range of fields and unifying principles that explain the structure, function, growth, History of life, origin, evolution, and ...
, pharmacology, disease, and
physiology Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...
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 Systems pharmacology is the application of systems biology principles to the field of pharmacology. It seeks to understand how drugs affect the human body as a single complex biological system. Instead of considering the effect of a drug to be the ...
,
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 describing how the body affects a specific su ...
,
pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...
and disease progression with a focus on
populations Population is a set of humans or other organisms in a given region or area. Governments conduct a census to quantify the resident population size within a given jurisdiction. The term is also applied to non-human animals, microorganisms, and pl ...
and
variability Variability is how spread out or closely clustered a set of data is. Variability may refer to: Biology *Genetic variability, a measure of the tendency of individual genotypes in a population to vary from one another *Heart rate variability, a phy ...
. 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 In linguistics, a neologism (; also known as a coinage) is any newly formed word, term, or phrase that has achieved popular or institutional recognition and is becoming accepted into mainstream language. Most definitively, a word can be considered ...
, 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 an application of statistical methods to economic data in order to give empirical content to economic relationships. M. Hashem Pesaran (1987). "Econometrics", '' The New Palgrave: A Dictionary of Economics'', v. 2, p. 8 p. 8 ...
". 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 potency or effect of a substance by its effect on animal testing, living animals or plants (''in vivo''), or on living cells or tissues (''in vitro''). A bioassay can be either quantal or quantit ...
; 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)

Pharmacokinetic 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 describing how the body affects a specific subs ...
models are constructs aimed at characterizing the average pharmacokinetic behavior of a drug within a population. By incorporating inter-individual variability, these models provide insights into central tendencies and variabilities in drug responses across diverse patient groups. Their application extends to the optimization of dosing regimens at a population level.


Pharmacodynamics (PD)

Pharmacodynamic Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...
models focus on elucidating the intricate relationship between drug concentration and its effects on the body. This includes both the desired therapeutic effects and potential side effects. By delineating the time course of drug effects, these models contribute to the prediction of efficacy and adverse events, aiding in the identification of optimal dosing strategies.


Physiologically based Pharmacokinetics

Physiologically-Based Pharmacokinetic models integrate physiological information to simulate drug behavior in various tissues and organs. These models consider organ-specific blood flow, tissue permeability, and drug properties, facilitating predictions of drug concentration at specific sites. PBPK models are instrumental in understanding complex drug behaviors.


Exposure-response

Exposure-Response models establish the relationship between drug exposure and clinical response. They play a crucial role in determining the optimal therapeutic range and predicting the likelihood of efficacy or adverse events. These models not only guide dose individualization based on desired clinical outcomes but also provide information on population exposure-response relationships for effects and adverse effects.


Drug-Drug Interaction

Drug-Drug Interaction models explore the impact of interactions between different drugs on their pharmacokinetics or pharmacodynamics. These models help predict the effects of co-administered drugs on each other, aiding in the identification of potential risks and the adjustment of dosages in the presence of multiple medications.


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 is evidence obtained through sense experience or experimental procedure. It is of central importance to the sciences and plays a role in various other fields, like epistemology and law. There is no general agreement on how t ...
, semi-mechanistic, and
systems biology Systems biology is the computational modeling, computational and mathematical analysis and modeling of complex biological systems. It is a biology-based interdisciplinary field of study that focuses on complex interactions within biological system ...
. 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 refers to any model which assumes linearity in the system. The most common occurrence is in connection with regression models and the term is often taken as synonymous with linear regression model. However, t ...
when the change of disease status over time is assumed to be constant.


Systems Pharmacology

Systems Pharmacology models integrate pharmacokinetics, pharmacodynamics, and systems biology to provide a comprehensive understanding of drug effects. By considering the intricate interplay between drugs, biological systems, and disease pathways, these models contribute to a holistic approach to drug development and personalized medicine.


Mechanistic Models

Mechanistic models provide a detailed understanding of the underlying biological and physiological processes governing drug behavior. These models offer insights into the mechanisms influencing drug absorption, distribution, metabolism, and elimination, aiding in predicting drug responses in diverse scenarios.


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 American(s) may refer to: * American, something of, from, or related to the United States of America, commonly known as the "United States" or "America" ** Americans, citizens and nationals of the United States of America ** American ancestry, p ...
(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 International is an adjective (also used as a noun) meaning "between nations". International may also refer to: Music Albums * ''International'' (Kevin Michael album), 2011 * ''International'' (New Order album), 2002 * ''International'' (The T ...
(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 medication, medicines. It is a miscellaneous science as it ...
,
Clinical pharmacology Clinical pharmacology is "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". Clinical pharmacology ...
,
Statistics Statistics (from German language, German: ', "description of a State (polity), state, a country") is the discipline that concerns the collection, organization, analysis, interpretation, and presentation of data. In applying statistics to a s ...
,
Medicine Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injury or disease, ...
, or
Engineering Engineering is the practice of using natural science, mathematics, and the engineering design process to Problem solving#Engineering, solve problems within technology, increase efficiency and productivity, and improve Systems engineering, s ...
. The first professor of pharmacometrics was Mats Karlsson,
Uppsala University Uppsala University (UU) () 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 operation. Initially fou ...
.


Journals

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


References

{{reflist Pharmaceutical industry Pharmacodynamics Pharmacokinetics