Pocket Lexicon of Clinical Pharmacology

with biostatistical terminology

Edited by:Géza LaknerBéla GachályiJúlia Singer

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Editors:

Lakner, Géza dr.Gachályi, Béla dr.Singer, Júlia dr.

Authors:

Pocket lexicon of clinical pharmacology

Gachályi, Béla dr.Lakner, Géza dr.

Vereczkey, László dr.

Biostatistical terminology

Boda, Krisztina dr.Hajtman, Béla dr.

Lang, ZsoltReiczigel, Jen dr.ő

Singer, Júlia dr.Vargha, Péter

Review:

Vas, Ádám dr.

Special thanks to:

Árvay, Krisztina dr. Mathiász, Dóra dr.Bors, Zsuzsa dr. Nagy, Lajos dr.

Borvendég, János dr. Paál, Tamás dr.Bölcsvölgyi, Tamás dr. Polecsák, Mária dr.Eggenhofer, Judit dr. Róna, Kálmán dr.

Elek, Sándor dr. Sági, ZsuzsannaKarányi, Zsolt Sipos, Adrien dr.

Kovács, Péter dr.

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Contents

INTRODUCTION.......................................................................................................... .4

POCKET LEXICON..................................................................................................... .6

ACRONYMS AND SYMBOLS.................................................................................. .12

THEMATICAL INDEX................................................................................................ .14

LITERATURE............................................................................................................. .16Clinical pharmacology......................................................................................................................17Biostatistics.......................................................................................................................................23

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Introduction

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The Pocket Lexicon of Clinical Pharmacology collects over 800 terms and synonyms from the interdisciplinary field of clinical pharmacology and medical research-related aspects of biostatistics. 500+ entries represent a comprehensive coverage of general clinical pharmacology, human drug development, Evidence Based Medicine, pharmacokinetics and pharmacodynamics, pharmacoeconomy, pharmacoepidemiology, pharmacogenetics and chronopharmacology, as well as important organizations and institutional research formations.

The author team of the Hungarian Society for Clinical Biostatistics has selected 300+ notions in biostatistics and applied numeric analytical methods with detailed descriptions, providing a valuable intellectual asset for the Pocket Lexicon.

Structure of the book

The Pocket Lexicon contains entries in following format: term (acronym) [topic]

Body text is typesetted as plain text. Concepts discussed in current article are formatted in bold-face. Bold-italic highlighting is articulatory. Expressions shown in italic are cross-referenced at the end of current entry (cross-references).---> cross-references

Next, Acronyms and symbols section contains phrasings for mathematical-biostatistical, biochemical and pharmaceutical tokens, and exposes various common and less common abbreviations and acronyms.

The Thematical index provides a quick and easy way to execute thematized searches.

The volume ends with Literature references.

The Pocket Lexicon of Clinical Pharmacology targets various professionals - medical doctors, pharmacists, biologists, biostaticians - engaged in human drug development and clinical research, practizing physicians with special interests in this interdisciplinary science and medical students. In this textbook we sincerely present to the Reader the best of clinical pharmacology as an intersection of an applied pharmaceutical science, a clinical entity and human research methodology.

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Pocket lexicon

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absolute risk reduction (ARR) [EBM]

The absolute arithmetic difference in the event rates of a target variable (endpoint, outcome) between the experimental and the control group. ARR = |EER-CER| , where EER is the experimental event rate, CER is the control event rate.---> absolute risk, event rate, relative risk reduction

ADME [GEN]

The pharmacokinetic plot (graphical representation of drug concentration over time) is a summation of four processes running parallel in the body: Absorption, Distribution, Metabolism and Elimination. The acronym ADME reflects these processes which ultimatively determine the fate of drugs in an organism. An ADME-study is a human study aimed at the observation of pharmacokinetic properties of a drug candidate,---> absorption, distribution, metabolism, elimination

antagonism [PKPD]

~ is a type of drug interaction where the pharmacological effects of some or all concomittantly administered drugs diminish. The ~ may be reversible or irreversible. A different classification for ~s is:• Competitive: The two drugs in interaction connect at the same binding site of the same

receptor, e.g. acetylcholin vs. atropine. In this case the antagonist drug shows affinity to the given binding site but it does not express intrinsic activity (for comparison, see: agonist).

• Noncompetitive: The two drugs fix at different binding sites of the same receptor or at different receptors, e.g. papaverine in higher doses attaches to muscarinerg receptors.

• Indirect: The interacting drug fixes itself on the allosteric binding site.• Competitive-noncompetitive: The antagonist compound acts a competitive one in lower

doses and turns noncompetitive in higher concentrations, e.g. acetylcholine vs. papaverine.

• Functional: Two agonist pharmacons exert opposing effects on different receptors in the same organ / tissue, e.g. histaminergic and β2-adrenergic combined effect on bronchial

musculature.• Physiological: Two agonist pharmacons produce opposing effects on different receptors

of different organs / tissues, e.g. combined effect of the indirect vasopressor activity of heart glycosides and vasodilator activity of hydralazine.

• Chemical: One compound enters into chemical reaction with an another and deactivates the latter regardless of being bound to a receptor or not. Several antidotes, commonly used in oxyology and toxicology fall into this category, e.g. protamine, chelating agents, dimercaptol.

---> agonist

bioavailability [PKPD]

The percentage of total amount of drug administered reaching the systemic circulation in unchanged form. The ~ of intravenous application is 100%, in case of other administration routes - due to absorption and first pass metabolism - it varies and can be remarkably lower than 100%.---> absorption, “first pass” metabolism

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biorhythm [GEN]

~ is the cyclic-periodic biological activity of an organism aimed at the accomodation of the organism to changing environment, hence enhancing survival. Classification:

● by pacemaker of biological rhythm: ● exogenic (external)● endogenic (internal)

● by periodic time: ● ultradian (shorter than a day, e.g. part of day, ebb and flow)● circadian (cca. 24 hours)● infradian (longer than a day)● circaseptan (weekly)● circatrigintan (monthly)● circalunar (lunar month)● circaseasonal (seasonal)● circannual (yearly)

Special presentation of ultradian rhythms are tidal rhythms with phase shift, like phase advance and phase delay. Phase shift may be encountered when flying over multiple time zones on airplane (jet lag) or in case of shift work (night shift). It is thought to be easier to fly from east to west as the day extends (phase delay), rather than the opposite direction, when the day gets reduced (phase advance). A phase delay approach in shift work is also recommended: when changing shifts, it is more advisable to move to a later shift than to an earlier one. Moreover, the slow rotation of shifts is a more beneficial approach than a fast turnover.---> chronopharmacology

blind study [EBM]

Blinding is a study design technique where one or more parties of the clinical study are not informed about the allocation of treatments among trial subject groups (who receives active compound, who receives placebo).

● single blind study: the only uninformed party is the patient● double blind study: neither the subject nor the investigators are in the know of

treatment allocation ● triple blind study: in some special cases even the monitor / sponsor and those who

are responsible for data analysis are uninitiated.The aim of blinding is elimination of subjective factors during observation and analysis, therefore reducing bias. A blind design should be implemented with care, because active and control treatments are to be produced to remain visually indistinguishable and identical regarding their dosing scheme (number of tablets, frequency of administration) which postulates solid manufacturing and accurate organization. If the study drugs in a clinical trial with multiple active therapy arms could not be transformed to be visibly identical (color, shape, formulation), the preparations – depending on their size and formulation – may be hidden in capsules, although this manipulation may yield in gross variations of pharmacokinetic properties. Encapsulation may thus not be the first choice in early phase human studies where pharmacokinetic behavior is a prime question. In this setting the double dummy, or masked administration technique comes handy: a visually

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indistinguishable placebo complement will be manufactured to each active treatment and – if the therapeutic regimes of the active compounds differ – the regimes will also be merged. A novel study design scheme is the Prospective Randomized Open Blinded Endpoint (PROBE) study. The identity of treatments is known to both the patients and researchers but a blinded endpoint committee evaluates the applicable study endpoints. PROBE is similar to a double blind study arrangement regarding its evaluation but it mimics more realistically common medical practice yet being even more cost-effective.

blockbuster drug [GEN]

~s are defined as drugs with 1 billion USD or more in sales revenue during their whole product life-cycle. Mega-blockbusters bring the $1 billion plus in revenue yet in their first year of marketing.

case-control study [EBM]

A study design where the treatment groups are identified by the presence or absence of a particular outcome and the exposure will be analysed retrospectively:

● case group (or cases): patients showing the predefined outcome, i.e. in whom the endpoint in question has occurred

● control group (or controls): in whom the predefined outcome has not occurred.---> observational study

clearance [PKPD]

The amount of plasma which is being “cleared” from a xenobiotic via a certain elimination route (e.g. hepatic, renal).

Total body clearance

CLD

AUCT =

− ∞0 , where D is the dose, AUC0-∞ is the area under the curve.

Renal clearance:

CLU

DCLR T= ⋅ , where U is the total amount of drug excreted in the urine.

Organ clearance (e.g. liver: CLH)CLorgan = Q · E , where Q is the blood flow of the organ, E is the extraction ratio.

Concerning the liver, as a principal party in drug elimination, the drugs can be divided in two groups according to their clearance:

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● high clearance or perfusion-limited compounds (E > 0.8, e.g. propranolol, lidocain), where the elimination is limited by only the hepatic blood flow not the extraction ratio

● low clearance or extraction-limited drugs (E < 0.2, e.g. diazepam), where the drug metabolizing enzyme capacity is the rate limiting factor of the elimination.

---> extraction ratio, elimination, well-stirred model

clinical trial, clinical study (CT) [EBM]

A ~ is medical research conducted in human subjects aimed at the discovery, verification or refinement of the

● pharmacological, clinical- pharmacodynamic effects and/or● pharmacokinetic properties (ADME) and/or● safety profile of a candidate drug.

A ~ is an arrangement for obtaining sound arguments upon a drug’s harmlessness and clinical effectiveness. The terms clinical trial and clinical study are synonymous. In a narrower sense, however, under the term of clinical pharmacology (or preclinical) study pharmacokinetic-safety studies (like phase I or in some cases phase IIa studies) are understood, while phase IIb/III/IV studies are classifed as being ~s.---> ADME, controlled study, observational study, pharmacodynamics, phase I study, phase II study, phase III study, phase IV study, preclinical study, study drug

controlled study [EBM]

A study is controlled when the findings of a treatment group (or treatment groups) are compared to the results of a control group.In prospective studies the control group may be an

● active control group who receive a reference drug or a● placebo control group receiving blank - placebo - preparation.

In reports of retrospective studies the term historical control group may be encountered. In this setting the researcher analyzes past medical documentation, originating from routine medical care and the classification into treatment or control group results from historical data of past exposure.---> case-control study, confirmatory trial, observational study, placebo, randomized controlled clinical trial

essentially similar product [GEN]

A product is regarded as being essentially similar to the original if● the qualitative and quantitative composition of their active ingredients are the same● they are produced in the same drug formulation● the two products are biologically equivalent.

---> bioequivalence, equivalence, generic product

“first pass” metabolism [PKPD]

Drugs entered into the body not directly via blood stream (e.g. by oral route or injected intramuscularly) undergo metabolism in the intestinal mucosa and/or liver prior to reaching the systemic circulation. When applying the same doses per os and intravenously the AUC

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(area under the plasma drug concentration-time curve) for oral administration will be lower than that of the i.v. administration, hence lower the bioavailability.The ~ is a decisive factor upon oral administration, though its effects on various pharmacokinetic parameters should not be neglected in case of intraperitoneal route, either. Rectal administration seems to be an inherently favorable option, because the vena rectalis inferior - playing a prime part in absorption - inosculates into the vena cava inferior, bypassing the vena hepatica system (N.B. Vena rectalis superior and media are branching yet into vena hepatica!). The sublingual administration also minimizes ~ due to branching of vena lingualis into vena azygos / vena cava superior reservoir system.---> bioavailability, area under the plasma drug concentration-time curve, drug metabolism

orphan drug [GEN]

~s are pharmacological entities developed for curing rarely occurring diseases (frequency: USA: < 200 000 patients in total population; EU: < 5 patients / 10 000 inhabitants) like Huntington-chorea, myoclonus, amyotrophic lateralsclerosis, Tourette-syndrome and some muscular dystrophies. Current drug development is based on a statistical approach – the “one drug fits all” principle, because development costs for a small target patient population may not be justified, even in case of market exclusivity. ~ production is rewarded by ensuring benefits for ~ companies through a legislative way (Orphan Drug Act).

pharmacovigilance [GCP]

~ is the continuous tracking of drug treatment safety – monitoring, evaluation and actions taken in the know of safety-related data. ~ in its original context covers activities for recognition, assessment and prevention of adverse drug reactions but in a broader sense, beyond the safety of pharmaceuticals, it includes safety management of herbal extracts (phytovigilance), therapeutic agents of alternative medicine (homeovigilance), blood products (haemovigilance), vaccines (vaccinovigilance), and medical devices (materiovigilance). The ~ also weighs the safety profile of inactive components of therapeutic products (i.e. excipients) and their contribution to safety profile of the whole product. Moreover, ~ oversees the environmental effects of therapeutic products, their possible role in the pollution and also takes drug residuals (e.g. antibiotics, steroides) found in food products of animal origin under scrutiny. Methods for safety monitoring include:

● pre-approval surveillance: system of obligatory expedited adverse event reporting in conjunction with clinical trials, according to ICH-GCP, with special attention to Suspected Unexpected Serious Adverse Reactions (SUSAR)

● postmarketing / post-approval surveillance● passive: voluntary information sources, like spontaneous adverse events

reporting, causality assessment of case-series, literature review, database searches● intensified adverse event reporting: as an extension to spontaneous adverse

events reporting, the marketing authorisation holder may initiate a “campagin” for a shorter time frame (e.g. 6 months), immediately following introduction of a drug product

● active: updates of safety profile with Periodic Safety Update Reports (PSUR) issued by marketing authorisation holder

● research in pharmacoepidemiology

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● drug utilization study (DUS):  applied interdisciplinary research technique of pharmacoepidemiology and pharmacoeconimcs, conducted in special populations or patient groups (e.g. children, elderly people, patients suffering from parenchymal diseases; stratification by e.g. gender, age, concomittant medication) to reveal clinical, social and economic aspects and interrelations of drug therapy.

The corrective actions of ~ include alert letters (for manufacturers, clinicians or communication to the public) or modifications to the Summary of Product Characteristics or – as an ultimate measure – withdrawal of marketing authorisation.--> adverse drug reaction, adverse event reporting, marketing authorisation holder, Periodic Safety Update Report, pharmacoeconomics, pharmacoepidemiology, postmarketing surveillance, spontaneous adverse event reporting, Suspected Unexpected Serious Adverse Reaction

phase I study [EBM]

~s are principally pharmacological (preclinical) tolerability or safety studies. The principal aim of these studies is the determination of human tolerability - side effect profile, pharmacokinetics and in some cases pharmacodynamic effects of the study drug. ~ are required in the following cases:

● first human administration of a novel chemical entity,● change in formulation of a previously authorised product,● exploration of pharmacokinetics in subjects with altered metabolism (e.g. in patients

with liver or kidney disease).The trial subjects in a ~ are primarily healthy male volunteers. In some special clinical settings - like human research of antiretroviral products or cytostatics - due to the unjustified, extreme high risk associated with the administration of such potentially toxic compounds to healthy subjects, the participants of oncology and HIV trials are patients suffering from the target disease.---> exploratory trial, study drug, trial subject

Proof Of Concept (Proof Of Principle) study (POC) [EBM]

● In vitro essays or animal models during the preclinial phase of drug development which determine the pharmacological effect of a compound.

● During the human clinical trials, ~s confirm the pharmacological activity and/or clinical efficacy of the drug explored by preclinical data or former (early phase) human studies. The ~s, based on exploratory studies provide evidences of the highest grade in the hierarchy of clinical evidences.

---> confirmatory trial, Evidence Based Medicine, exploratory study

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Acronyms and symbols

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(lambda1 , alpha) distribution rate constant

(lambdaz , beta, gamma)

apparent elimination rate constant

(tau) time interval at repeated administration

ADME Absorption, Distribution, Metabolism, Excretion

ADR adverse drug reaction

AE adverse event, adverse experience

AFID alkali flame ionization detector

ARR absolute risk reduction

AUC Total Area Under the plasma drug concentration-time Curve

aVd apparent volume of distribution

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Thematical index

[EBM] Evidence Based Medicine

[GCP] Good Clinical Practice

[GEN] General clinical pharmacology

[ORG] Organisations, institutions

[PE] Pharmacoeconomy

[PG] Pharmacogenomics

[PKPD] Pharmacokinetics-pharmacodynamics

[STAT] Biostatistics

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[...]

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Literature

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Clinical pharmacology

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