Leon Aarons

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Leon Aarons
Born
Leon Aarons

 (2024-02-21UTC00:42:37)
NationalityAustralian
Education
  • BSc Sydney (1968) MSc University of Calgary (1971) PhD University of Manchester (1973)
Known forpharmacometrics
Scientific career
Institutions University of Manchester
Thesis Theoretical Chemistry

Leon Aarons is an Australian chemist who researches and teaches in the areas of pharmacodynamics and pharmacokinetics. [1] He lives in the United Kingdom and from 1976 has been a professor of pharmacometrics at the University of Manchester. [2] 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. [2] From 1985 to 2010 Aarons was an editor emeritus of the Journal of Pharmacokinetics and Pharmacodynamics [3] and is a former executive editor of the British Journal of Clinical Pharmacology . [4]

Contents

Contribution to pharmacology

Data modelling

Much of Aarons' work focuses on building an understanding of how the effects of drugs or toxic agents are managed in humans. In 2009 he co-authored a paper that aimed to explore an approach to the modelling of effects on people by drugs and toxic agents "based on the underlying physiology and pathology of the biological processes,...[ and to review]...the current status of pharmacodynamic and pharmacokinetic modelling, and outline a conceptual framework that may be helpful in advancing the field." [5] A model was proposed that included the kinetics of the substance as a part of the process. To some extent, this was a challenge to the widely accepted dose/effect concept in pharmacology and toxicology at the time which assumed that the exposure/dose of a drug or a toxin is related to the effects on the patient, beneficial or toxic. The paper explained the purposes of data modelling as being to describe complex data, test hypotheses and make predictions, and noted when a drug interacts with a patient, there is a "chain of events at the molecular level, cellular level, organ/physiological system level, and whole-body level...[and ]... in principle, modelling may be performed at each of these levels." The effect on a patient could be therapeutic or possibly result in adverse outcomes. The authors concluded that including the systems biology model they discussed in the paper into conventional PKPD modelling would require further collaboration to make it robust but able to be clearly defined. [5]

Design of scientific investigations

Aarons has defined pharmacokinetics (PK) as the study of the complex chain of events that links a dose of drugs administered to a patient and the expected effect or response. PK is based on analysing the concentration of drugs and tracking how they are absorbed, distributed, metabolised and excreted within the patient. [6] Some of his work has involved using optimal design theory to explore what makes a successful scientific investigation for pharmacokinetic studies and has said that this "involves the selection and a careful balance of a number of design factors, including the number and location of measurement times and the number of subjects to include in the study." [7] According to Aarons, population pharmacokinetics studies which focus on what happens to the substances administered to a patient would need specific design factors that apply "statistical experimental design principles to non-linear population pharmacokinetic models." [8] A later paper co-authored by Aarons, reviews the different approaches to optimal design of population pharmacokinetic and pharmacodynamic experiments and notes that some of the options may raise concerns at to their practicality. The paper did, however, conclude "that as the awareness about the benefits of this approach increases, more people will embrace it and ultimately will lead to more efficient population pharmacokinetic and pharmacodynamic experiments." [9]

Enterohepatic circulation

Research by Aarons has focused on enterohepatic cycling (EHC) which refers to the process whereby a drug goes through the liver and biliary tract for excretion and is released into the small intestine, where it can be reabsorbed back into circulation and subsequently returned to the liver. This can cause liver damage and the half-life and duration of a drug to be increased. Aarons and his team stressed that knowing the extent of EHC is invaluable in deciding whether or not the in vitro characteristics of a drug - i.e. those taking place outside of a living organism - will have any effect on the overall process of absorption in vivo, or when it is taking place inside the organism. [10] Aarons had earlier been involved in research on the area under the curve (AUC). This is a pharmacokinetic statistic used to describe the total exposure to a drug - specifically the concentration of a drug in body fluids such as blood - and is useful because it gives insight into the extent of exposure to a drug and its clearance rate from the body. The research was seen as important in the "design of sampling protocols for accurate determination of AUC(0– ∞) for drugs subject to enterohepatic cycling." [11]

Drug-drug interactions

Drug−drug interactions (DDI) are one of the primary causes of adverse drug reactions which can result in serious health issues. In 1981, Aarons said that because of the practice at the time of multiple drug therapy, there was a good chance of drug-drug interaction. He reviewed the literature around pharmacokinetic interactions when there is a change of the disposition of the interacting drugs, in particular, the mechanisms that cause these changes. He noted that in drug-drug interactions both drugs are often affected, and it is necessary to develop "a model that describes the disposition of all interacting species." [12] In 2011 Aaron was part of a team that critiqued the then two-fold method of assessing drug-drug interaction and proposed that there would be less bias if predictions were made using a wider range of data collected and the allowance of variability was included in the process. [13] A research programme in 2017 that Aarons was involved in explored the mechanistic prediction of the oral bioavailability differences observed between the original formulation of a drug and that on its release. The study predicted that bioavailability of the original drug was due to reduced deactivation by an enzyme CYP3A4 in the intestine This was proven in the study, which concluded that "this work highlights the importance that formulations can have [when there are] clinically-relevant DDI involving CYP3A substrates...[and that]... this aspect is generally overlooked when evaluating DDIs in drug development." [14] Aarons had collaborated on earlier research published in 2008 used physiologically based pharmacokinetic modelling (PBPK) to "evaluate the potential CYP3A4 inhibitory effect of a drug in development." [15] There had been a paper that described the methodology of the trial, [16] and the second paper analysed the results, which showed that although the drug-drug interaction was slightly less than predicted, valuable assessment of the interaction was achieved and could be applied in drug development. [15]

Related Research Articles

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

Pharmacology is a science of medical drug and medication, 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.

<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.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

<span class="mw-page-title-main">Preclinical development</span> Stage of drug development

In drug development, preclinical development is a stage of research that begins before clinical trials and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals.

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">Physiologically based pharmacokinetic modelling</span>

Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique for predicting the absorption, distribution, metabolism and excretion (ADME) of synthetic or natural chemical substances in humans and other animal species. PBPK modeling is used in pharmaceutical research and drug development, and in health risk assessment for cosmetics or general chemicals.

<span class="mw-page-title-main">Acecainide</span> Antiarrythmic drug

Acecainide is an antiarrhythmic drug. Chemically, it is the N-acetylated metabolite of procainamide. It is a Class III antiarrhythmic agent, whereas procainamide is a Class Ia antiarrhythmic drug. It is only partially as active as procainamide; when checking levels, both must be included in the final calculation.

<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.

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, 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.

<span class="mw-page-title-main">Tabimorelin</span> Chemical compound

Tabimorelin (INN) is a drug which acts as a potent, orally-active agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and growth hormone secretagogue, mimicking the effects of the endogenous peptide agonist ghrelin as a stimulator of growth hormone (GH) release. It was one of the first GH secretagogues developed and is largely a modified polypeptide, but it is nevertheless orally-active in vivo. Tabimorelin produced sustained increases in levels of GH and insulin-like growth factor 1 (IGF-1), along with smaller transient increases in levels of other hormones such as adrenocorticotropic hormone (ACTH), cortisol, and prolactin. However actual clinical effects in adults with growth hormone deficiency were limited, with only the most severely GH-deficient patients showing significant benefit, and tabimorelin was also found to act as a CYP3A4 inhibitor which could cause it to have undesirable interactions with other drugs.

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.

Biosimulation is a computer-aided mathematical simulation of biological processes and systems and thus is an integral part of systems biology. Due to the complexity of biological systems simplified models are often used, which should only be as complex as necessary.

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.

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

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<span class="mw-page-title-main">Charles Flexner</span> American physician and pharmaceutical scientist

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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.

<span class="mw-page-title-main">Talmage Egan</span> American academic

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References

  1. ↑ "Personal Information: Leon Aaron" (PDF). eropass. Retrieved 13 November 2020.
  2. 1 2 "Prof Leon Aarons BSc, MSc, PhD | The University of Manchester". research.manchester.ac.uk. Retrieved 3 November 2017.
  3. ↑ "Journal of Pharmacokinetics and Pharmacodynamics - Editors". Springer. Retrieved 12 November 2020.
  4. ↑ "Professor Leon Aarons - Worldwide Antimalarial Resistance Network". www.wwarn.org. 11 August 2016. Retrieved 7 September 2017.
  5. 1 2 Dahl, Svein G.; Aarons, Leon; et al. (15 December 2009). "Incorporating Physiological and Biochemical Mechanisms into Pharmacokinetic–Pharmacodynamic Models: A Conceptual Framework". Basic & Clinical Pharmacology & Toxicology. 106 (1 January 2010): 2–12. doi:10.1111/j.1742-7843.2009.00456.x. PMID   19686541.
  6. ↑ Aarons, Leon. "Basic Concepts in Pharmacokinetics: Lecture (2015)" (PDF). The University of Manchester. Retrieved 15 November 2020.
  7. ↑ Aarons, Leon; Ogungbenro, Kayode (20 January 2010). "Optimal design of pharmacokinetic studies". Basic & Clinical Pharmacology & Toxicology. 106 (3): 250–255. doi: 10.1111/j.1742-7843.2009.00533.x . PMID   20102362.
  8. ↑ Ogungbenro, K.; Aarons, L. (October–November 2007). "Design of population pharmacokinetic experiments using prior information". Xenobiotica. 37 (10–11): 1311–1330. doi:10.1080/00498250701553315. PMID   17968747.
  9. ↑ Ogungbenro, Kayode; Dokoumetzidis, Aristides; Aarons, Leon (July–September 2009). "Application of optimal design methodologies in clinical pharmacology experiments". Pharmaceutical Statistics. 8 (3): 239–252. doi:10.1002/pst.354. PMID   19009585. S2CID   43012247.
  10. ↑ Shepard, Theresa A.; Lockwood, Graham F.; Aarons, Leon J.; et al. (1 June 1989). "Mean residence time for drugs subject to enterohepatic cycling". Journal of Pharmacokinetics and Biopharmaceutics. 17 (3): 327–345. doi:10.1007/BF01061900. PMID   2810071. S2CID   19219083.
  11. ↑ Shepard, Theresa A.; Reuning, Richard H.; Aarons, Leon J. (1 December 1985). "Estimation of area under the curve for drugs subject to enterohepatic cycling". Journal of Pharmacokinetics and Pharmacodynamics. 13 (6): 589–608. doi:10.1007/BF01058903. PMID   3834073. S2CID   37498743.
  12. ↑ Aarons, Leon (February 1981). "Kinetics of Drug-Drug Interactions". Pharmacology & Therapeutics. 14 (3): 321–334. doi:10.1016/0163-7258(81)90031-0. PMID   7034002.
  13. ↑ Guest, Eleanor J.; Aarons, Leon; et al. (February 2011). "Critique of the Two-Fold Measure of Prediction Success for Ratios: Application for the Assessment of Drug-Drug Interactions". Drug Metabolism and Disposition. 39 (2): 170–173. doi:10.1124/dmd.110.036103. PMID   21036951. S2CID   14269107.
  14. ↑ Olivares-Morales, Andres; Aarons, Leon; Rostami-Hodjegan, Amin. "Formulations can have an impact on intestinal drug-drug interactions: A PBPK study using oxybutynin as a model drug" (PDF). www.cetara.com. Retrieved 17 November 2020.
  15. 1 2 Chenel, Marylore; Bouzom, Francios; Cazade, Fanny; Ogungbenro, Kayode; Aarons, Leon; Mentre, France (December 2008). "Drug-drug interaction predictions with PBPK models and optimal multiresponse sampling time designs: application to midazolam and a phase I compound. Part 2: clinical trial results". Journal of Pharmacokinetics and Pharmacodynamics. 35 (6): 661–681. doi:10.1007/s10928-008-9105-5. PMC   2797537 . PMID   19130187.
  16. ↑ Chenel, Marylore; Bouzom, Francios; Aarons, Leon; Ogungbenro, Kayode (December 2008). "Drug-drug interaction predictions with PBPK models and optimal multiresponse sampling time designs: application to midazolam and a phase I compound. Part 1: comparison of uniresponse and multiresponse designs using PopDes". Journal of Pharmacokinetics and Pharmacodynamics. 35 (6): 661–681. doi:10.1007/s10928-008-9104-6. PMID   19130188. S2CID   11420549.
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