Pharmacometrics

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Pharmacometrics is a field of study of the methodology and application of models for disease and pharmacological measurement. It uses mathematical models of biology, pharmacology, disease, and physiology to describe and quantify interactions between xenobiotics and patients (human and non-human), including beneficial effects and adverse effects. [1] It is normally applied to quantify drug, disease and trial information to aid efficient drug development, regulatory decisions and rational drug treatment in patients.

Contents

Pharmacometrics uses models based on pharmacology, physiology, and disease for quantitative analysis of interactions between drugs and patients. This involves Systems pharmacology, pharmacokinetics, pharmacodynamics and disease progression with a focus on populations and variability.

Mould and Upton provide an overview of basic concepts in population modeling, simulation, and model-based drug development. [2]

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" [3] :

The sub-title of the book is, as far as we are aware, a neologism, 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". We hope it will prove useful for distinguishing the kind of measurement discussed and described in this book from what is nowadays called bioassay; 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 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 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 guide dose individualization based on desired clinical outcomes.

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. [4] There are three key classes of disease progression models: empirical, semi-mechanistic, and systems biology. [5] Most of the disease progression models are empirical, describing disease trajectory rather than the physiological background of the disease. [6] The simplest model that is used to describe disease progression is a linear model 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. [7]

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. [8] Regional groups include PAGE in Europe [9] and PAGANZ in Australia and New Zealand. [10]

Pharmacometricians typically come from disciplines such as Pharmacy, Clinical pharmacology, Statistics, Medicine, or Engineering.

The first professor of pharmacometrics was Mats Karlsson, Uppsala University. [11]

Journals

The main journals that publish work in pharmacometrics are:

Related Research Articles

<span class="mw-page-title-main">Pharmacology</span> Branch of biology concerning drugs

Pharmacology is the science of medical drugs and medications, including a substance's origin, composition, pharmacokinetics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.

The therapeutic index is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect. The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction. The process of tolerance development is reversible and can involve both physiological factors and psychological factors.

<span class="mw-page-title-main">Pharmacodynamics</span> Area of Academic Study

Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms.

Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed. TDM aimed at improving patient care by individually adjusting the dose of drugs for which clinical experience or clinical trials have shown it improved outcome in the general or special populations. It can be based on a a priori pharmacogenetic, demographic and clinical information, and/or on the a posteriori measurement of blood concentrations of drugs (pharmacokinetic monitoring) or biological surrogate or end-point markers of effect (pharmacodynamic monitoring).

In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.

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 is inherently a translational discipline underpinned by the basic science of pharmacology, engaged in the experimental and observational study of the disposition and effects of drugs in humans, and committed to the translation of science into evidence-based therapeutics. It has a broad scope, from the discovery of new target molecules to the effects of drug usage in whole populations. The main aim of clinical pharmacology is to generate data for optimum use of drugs and the practice of 'evidence-based medicine'.

<span class="mw-page-title-main">Pharmacokinetics</span> Branch of pharmacology

Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific substance after administration. The substances of interest include any chemical xenobiotic such as pharmaceutical drugs, pesticides, food additives, cosmetics, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics is based on mathematical modeling that places great emphasis on the relationship between drug plasma concentration and the time elapsed since the drug's administration. Pharmacokinetics is the study of how an organism affects the drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models.

The following outline is provided as an overview of and topical guide to clinical research:

In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time. In practice, the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to estimate AUC. In pharmacology, the area under the plot of plasma concentration of a drug versus time after dosage gives insight into the extent of exposure to a drug and its clearance rate from the body.

PK/PD modeling is a technique that combines the two classical pharmacologic disciplines of pharmacokinetics and pharmacodynamics. It integrates a pharmacokinetic and a pharmacodynamic model component into one set of mathematical expressions that allows the description of the time course of effect intensity in response to administration of a drug dose. PK/PD modeling is related to the field of pharmacometrics.

Systems medicine is an interdisciplinary field of study that looks at the systems of the human body as part of an integrated whole, incorporating biochemical, physiological, and environment interactions. Systems medicine draws on systems science and systems biology, and considers complex interactions within the human body in light of a patient's genomics, behavior and environment.

In vitro to in vivo extrapolation (IVIVE) refers to the qualitative or quantitative transposition of experimental results or observations made in vitro to predict phenomena in vivo, biological organisms.

An in silico clinical trial, also known as a virtual clinical trial, is an individualized computer simulation used in the development or regulatory evaluation of a medicinal product, device, or intervention. While completely simulated clinical trials are not feasible with current technology and understanding of biology, its development would be expected to have major benefits over current in vivo clinical trials, and research on it is being pursued.

Quantitative systems pharmacology (QSP) is a discipline within biomedical research that uses mathematical computer models to characterize biological systems, disease processes and drug pharmacology. QSP can be viewed as a sub-discipline of pharmacometrics that focuses on modeling the mechanisms of drug pharmacokinetics (PK), pharmacodynamics (PD), and disease processes using a systems pharmacology point of view. QSP models are typically defined by systems of ordinary differential equations (ODE) that depict the dynamical properties of the interaction between the drug and the biological system.

Leon Aarons is an Australian chemist who researches and teaches in the areas of pharmacodynamics and pharmacokinetics. He lives in the United Kingdom and from 1976 has been a professor of pharmacometrics at the University of Manchester. In the interest of promoting the effective development of drugs, the main focus of his work is optimizing pharmacological models, the design of clinical studies, and data analysis and interpretation in the field of population pharmacokinetics. From 1985 to 2010 Aarons was an editor emeritus of the Journal of Pharmacokinetics and Pharmacodynamics and is a former executive editor of the British Journal of Clinical Pharmacology.

<span class="mw-page-title-main">Drug labelling</span>

Drug labelling is also referred to as prescription labelling, is a written, printed or graphic matter upon any drugs or any of its container, or accompanying such a drug. Drug labels seek to identify drug contents and to state specific instructions or warnings for administration, storage and disposal. Since 1800s, legislation has been advocated to stipulate the formats of drug labelling due to the demand for an equitable trading platform, the need of identification of toxins and the awareness of public health. Variations in healthcare system, drug incidents and commercial utilization may attribute to different regional or national drug label requirements. Despite the advancement in drug labelling, medication errors are partly associated with undesirable drug label formatting.

Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.

<span class="mw-page-title-main">Malcolm Rowland</span> British Pharmacologist

Malcolm Rowland FBPhS is Emeritus Professor of Pharmacy, University of Manchester, and Adjunct Professor, University of California San Francisco. His research in pharmacology, has been particularly in physiologically based pharmacokinetics. He has written several textbooks on the subject.

Target-mediated drug disposition (TMDD), is the process in which a drug binds with high affinity to its pharmacological target to such an extent that this affects its pharmacokinetic characteristics. Various drug classes can exhibit TMDD, most often these are large compounds but also smaller compounds can exhibit TMDD . A typical TMDD pattern of antibodies displays non-linear clearance and can be seen at concentration ranges that are usually defined as 'mid-to-low'. In this concentration range, the target is partly saturated.

References

  1. ↑ Barrett JS, Fossler MJ, Cadieu KD, Gastonguay MR (May 2008). "Pharmacometrics: a multidisciplinary field to facilitate critical thinking in drug development and translational research settings". Journal of Clinical Pharmacology. 48 (5): 632–49. doi:10.1177/0091270008315318. PMID   18440922. S2CID   32648945.
  2. ↑ Mould DR, Upton RN (September 2012). "Basic concepts in population modeling, simulation, and model-based drug development". CPT: Pharmacometrics & Systems Pharmacology. 1 (9): e6. doi:10.1038/psp.2012.4. PMC   3606044 . PMID   23835886.
  3. ↑ Laurence, D.R.; Bacharach, A.L. (1964). Evaluation of Drug Activities: Pharmacometrics. London: Academic Press.
  4. ↑ Ette EI, Williams PJ (2007). Pharmacometrics : the science of quantitative pharmacology. Hoboken, N.J.: John Wiley & Sons. ISBN   978-0-470-08796-1. OCLC   124040246.
  5. ↑ Cook SF, Bies RR (October 2016). "Disease Progression Modeling: Key Concepts and Recent Developments". Current Pharmacology Reports. 2 (5): 221–230. doi:10.1007/s40495-016-0066-x. PMC   5602534 . PMID   28936389.
  6. ↑ Schmidt S, Derendorf H (2014). Applied pharmacometrics. New York. ISBN   978-1-4939-1304-6. OCLC   897466424.{{cite book}}: CS1 maint: location missing publisher (link)
  7. ↑ Williams, PJ (2007). Pharmacometrics: The Science of Quantitative Pharmacology. John Wiley & Sons. p. 1.
  8. ↑ International Society of Pharmacometrics (ISoP)
  9. ↑ Population Approach Group Europe (PAGE)
  10. ↑
  11. ↑ "Uppsala Pharmacometrics". Uppsala University.
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