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<span>Drug development</span> </div> </a> <ul id="toc-Drug_development-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Range_of_therapeutic_indices" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Range_of_therapeutic_indices"> <div class="vector-toc-text"> <span class="vector-toc-numb">3</span> <span>Range of therapeutic indices</span> </div> </a> <button aria-controls="toc-Range_of_therapeutic_indices-sublist" class="cdx-button cdx-button--weight-quiet cdx-button--icon-only vector-toc-toggle"> <span class="vector-icon mw-ui-icon-wikimedia-expand"></span> <span>Toggle Range of therapeutic indices subsection</span> </button> <ul id="toc-Range_of_therapeutic_indices-sublist" class="vector-toc-list"> <li id="toc-Cancer_radiotherapy" class="vector-toc-list-item vector-toc-level-2"> <a class="vector-toc-link" href="#Cancer_radiotherapy"> <div class="vector-toc-text"> <span class="vector-toc-numb">3.1</span> <span>Cancer radiotherapy</span> </div> </a> <ul id="toc-Cancer_radiotherapy-sublist" class="vector-toc-list"> </ul> </li> </ul> </li> <li id="toc-Safety_ratio" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Safety_ratio"> <div class="vector-toc-text"> <span class="vector-toc-numb">4</span> <span>Safety ratio</span> </div> </a> <ul id="toc-Safety_ratio-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Synergistic_effect" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Synergistic_effect"> <div class="vector-toc-text"> <span class="vector-toc-numb">5</span> <span>Synergistic effect</span> </div> </a> <ul id="toc-Synergistic_effect-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Therapeutic_window" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Therapeutic_window"> <div class="vector-toc-text"> <span class="vector-toc-numb">6</span> <span>Therapeutic window</span> </div> </a> <ul id="toc-Therapeutic_window-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Optimal_biological_dose" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Optimal_biological_dose"> <div class="vector-toc-text"> <span class="vector-toc-numb">7</span> <span>Optimal biological dose</span> </div> </a> <ul id="toc-Optimal_biological_dose-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-Maximum_tolerated_dose" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#Maximum_tolerated_dose"> <div class="vector-toc-text"> <span class="vector-toc-numb">8</span> <span>Maximum tolerated dose</span> </div> </a> <ul id="toc-Maximum_tolerated_dose-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-See_also" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#See_also"> <div class="vector-toc-text"> <span class="vector-toc-numb">9</span> <span>See also</span> </div> </a> <ul id="toc-See_also-sublist" class="vector-toc-list"> </ul> </li> <li id="toc-References" class="vector-toc-list-item vector-toc-level-1 vector-toc-list-item-expanded"> <a class="vector-toc-link" href="#References"> <div class="vector-toc-text"> <span class="vector-toc-numb">10</span> <span>References</span> </div> </a> <ul id="toc-References-sublist" class="vector-toc-list"> </ul> </li> </ul> </div> </div> </nav> </div> </div> <div class="mw-content-container"> <main id="content" class="mw-body"> <header class="mw-body-header vector-page-titlebar"> <nav aria-label="Contents" class="vector-toc-landmark"> <div id="vector-page-titlebar-toc" class="vector-dropdown vector-page-titlebar-toc vector-button-flush-left" > <input type="checkbox" id="vector-page-titlebar-toc-checkbox" role="button" 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Available in 28 languages" > <label id="p-lang-btn-label" for="p-lang-btn-checkbox" class="vector-dropdown-label cdx-button cdx-button--fake-button cdx-button--fake-button--enabled cdx-button--weight-quiet cdx-button--action-progressive mw-portlet-lang-heading-28" aria-hidden="true" ><span class="vector-icon mw-ui-icon-language-progressive mw-ui-icon-wikimedia-language-progressive"></span> <span class="vector-dropdown-label-text">28 languages</span> </label> <div class="vector-dropdown-content"> <div class="vector-menu-content"> <ul class="vector-menu-content-list"> <li class="interlanguage-link interwiki-ar mw-list-item"><a href="https://ar.wikipedia.org/wiki/%D9%85%D8%A4%D8%B4%D8%B1_%D8%A7%D9%84%D8%B9%D9%84%D8%A7%D8%AC%D9%8A%D8%A9_(%D9%85%D9%86%D8%B3%D8%A8_%D8%B9%D9%84%D8%A7%D8%AC%D9%8A)" title="مؤشر العلاجية (منسب علاجي) – Arabic" lang="ar" hreflang="ar" data-title="مؤشر العلاجية (منسب علاجي)" data-language-autonym="العربية" data-language-local-name="Arabic" class="interlanguage-link-target"><span>العربية</span></a></li><li class="interlanguage-link interwiki-bg mw-list-item"><a href="https://bg.wikipedia.org/wiki/%D0%A2%D0%B5%D1%80%D0%B0%D0%BF%D0%B5%D0%B2%D1%82%D0%B8%D1%87%D0%B5%D0%BD_%D0%B8%D0%BD%D0%B4%D0%B5%D0%BA%D1%81" title="Терапевтичен индекс – Bulgarian" lang="bg" hreflang="bg" data-title="Терапевтичен индекс" data-language-autonym="Български" data-language-local-name="Bulgarian" class="interlanguage-link-target"><span>Български</span></a></li><li class="interlanguage-link interwiki-ca mw-list-item"><a href="https://ca.wikipedia.org/wiki/%C3%8Dndex_terap%C3%A8utic" title="Índex terapèutic – Catalan" lang="ca" hreflang="ca" data-title="Índex terapèutic" data-language-autonym="Català" data-language-local-name="Catalan" class="interlanguage-link-target"><span>Català</span></a></li><li class="interlanguage-link interwiki-cs mw-list-item"><a href="https://cs.wikipedia.org/wiki/Terapeutick%C3%BD_index" title="Terapeutický index – Czech" lang="cs" hreflang="cs" data-title="Terapeutický index" data-language-autonym="Čeština" data-language-local-name="Czech" class="interlanguage-link-target"><span>Čeština</span></a></li><li class="interlanguage-link interwiki-de mw-list-item"><a href="https://de.wikipedia.org/wiki/Therapeutische_Breite" title="Therapeutische Breite – German" lang="de" hreflang="de" data-title="Therapeutische Breite" data-language-autonym="Deutsch" data-language-local-name="German" class="interlanguage-link-target"><span>Deutsch</span></a></li><li class="interlanguage-link interwiki-es mw-list-item"><a href="https://es.wikipedia.org/wiki/%C3%8Dndice_terap%C3%A9utico" title="Índice terapéutico – Spanish" lang="es" hreflang="es" data-title="Índice terapéutico" data-language-autonym="Español" data-language-local-name="Spanish" class="interlanguage-link-target"><span>Español</span></a></li><li class="interlanguage-link interwiki-fr mw-list-item"><a href="https://fr.wikipedia.org/wiki/Index_th%C3%A9rapeutique" title="Index thérapeutique – French" lang="fr" hreflang="fr" data-title="Index thérapeutique" data-language-autonym="Français" data-language-local-name="French" class="interlanguage-link-target"><span>Français</span></a></li><li class="interlanguage-link interwiki-ko mw-list-item"><a href="https://ko.wikipedia.org/wiki/%EC%B9%98%EB%A3%8C%EC%9C%A0%ED%9A%A8%EB%9F%89" title="치료유효량 – Korean" lang="ko" hreflang="ko" data-title="치료유효량" data-language-autonym="한국어" data-language-local-name="Korean" class="interlanguage-link-target"><span>한국어</span></a></li><li class="interlanguage-link interwiki-hy mw-list-item"><a href="https://hy.wikipedia.org/wiki/%D4%B9%D5%A5%D6%80%D5%A1%D5%BA%D6%87%D5%BF%D5%AB%D5%AF_%D5%AB%D5%B6%D5%A4%D5%A5%D6%84%D5%BD" title="Թերապևտիկ ինդեքս – Armenian" lang="hy" hreflang="hy" data-title="Թերապևտիկ ինդեքս" data-language-autonym="Հայերեն" data-language-local-name="Armenian" class="interlanguage-link-target"><span>Հայերեն</span></a></li><li class="interlanguage-link interwiki-hi mw-list-item"><a href="https://hi.wikipedia.org/wiki/%E0%A4%9A%E0%A4%BF%E0%A4%95%E0%A4%BF%E0%A4%A4%E0%A5%8D%E0%A4%B8%E0%A4%95%E0%A5%80%E0%A4%AF_%E0%A4%B8%E0%A5%82%E0%A4%9A%E0%A4%95%E0%A4%BE%E0%A4%82%E0%A4%95" title="चिकित्सकीय सूचकांक – Hindi" lang="hi" hreflang="hi" data-title="चिकित्सकीय सूचकांक" data-language-autonym="हिन्दी" data-language-local-name="Hindi" class="interlanguage-link-target"><span>हिन्दी</span></a></li><li class="interlanguage-link interwiki-it mw-list-item"><a href="https://it.wikipedia.org/wiki/Indice_terapeutico" title="Indice terapeutico – Italian" lang="it" hreflang="it" data-title="Indice terapeutico" data-language-autonym="Italiano" data-language-local-name="Italian" class="interlanguage-link-target"><span>Italiano</span></a></li><li class="interlanguage-link interwiki-he mw-list-item"><a href="https://he.wikipedia.org/wiki/%D7%97%D7%9C%D7%95%D7%9F_%D7%AA%D7%A8%D7%A4%D7%95%D7%99%D7%98%D7%99" title="חלון תרפויטי – Hebrew" lang="he" hreflang="he" data-title="חלון תרפויטי" data-language-autonym="עברית" data-language-local-name="Hebrew" class="interlanguage-link-target"><span>עברית</span></a></li><li class="interlanguage-link interwiki-ml mw-list-item"><a href="https://ml.wikipedia.org/wiki/%E0%B4%9A%E0%B4%BF%E0%B4%95%E0%B4%BF%E0%B4%A4%E0%B5%8D%E0%B4%B8%E0%B4%BE_%E0%B4%B8%E0%B5%82%E0%B4%9A%E0%B4%BF%E0%B4%95" title="ചികിത്സാ സൂചിക – Malayalam" lang="ml" hreflang="ml" data-title="ചികിത്സാ സൂചിക" data-language-autonym="മലയാളം" data-language-local-name="Malayalam" class="interlanguage-link-target"><span>മലയാളം</span></a></li><li class="interlanguage-link interwiki-nl mw-list-item"><a href="https://nl.wikipedia.org/wiki/Therapeutische_breedte" title="Therapeutische breedte – Dutch" lang="nl" hreflang="nl" data-title="Therapeutische breedte" data-language-autonym="Nederlands" data-language-local-name="Dutch" class="interlanguage-link-target"><span>Nederlands</span></a></li><li class="interlanguage-link interwiki-ja mw-list-item"><a href="https://ja.wikipedia.org/wiki/%E6%B2%BB%E7%99%82%E6%8C%87%E6%95%B0" title="治療指数 – Japanese" lang="ja" hreflang="ja" data-title="治療指数" data-language-autonym="日本語" data-language-local-name="Japanese" class="interlanguage-link-target"><span>日本語</span></a></li><li class="interlanguage-link interwiki-pl mw-list-item"><a href="https://pl.wikipedia.org/wiki/Indeks_terapeutyczny" title="Indeks terapeutyczny – Polish" lang="pl" hreflang="pl" data-title="Indeks terapeutyczny" data-language-autonym="Polski" data-language-local-name="Polish" class="interlanguage-link-target"><span>Polski</span></a></li><li class="interlanguage-link interwiki-pt mw-list-item"><a href="https://pt.wikipedia.org/wiki/%C3%8Dndice_terap%C3%AAutico" title="Índice terapêutico – Portuguese" lang="pt" hreflang="pt" data-title="Índice terapêutico" data-language-autonym="Português" data-language-local-name="Portuguese" class="interlanguage-link-target"><span>Português</span></a></li><li class="interlanguage-link interwiki-ro mw-list-item"><a href="https://ro.wikipedia.org/wiki/Indice_terapeutic" title="Indice terapeutic – Romanian" lang="ro" hreflang="ro" data-title="Indice terapeutic" data-language-autonym="Română" data-language-local-name="Romanian" class="interlanguage-link-target"><span>Română</span></a></li><li class="interlanguage-link interwiki-ru mw-list-item"><a href="https://ru.wikipedia.org/wiki/%D0%A2%D0%B5%D1%80%D0%B0%D0%BF%D0%B5%D0%B2%D1%82%D0%B8%D1%87%D0%B5%D1%81%D0%BA%D0%B8%D0%B9_%D0%B8%D0%BD%D0%B4%D0%B5%D0%BA%D1%81" title="Терапевтический индекс – Russian" lang="ru" hreflang="ru" data-title="Терапевтический индекс" data-language-autonym="Русский" data-language-local-name="Russian" class="interlanguage-link-target"><span>Русский</span></a></li><li class="interlanguage-link interwiki-simple mw-list-item"><a href="https://simple.wikipedia.org/wiki/Therapeutic_index" title="Therapeutic index – Simple English" lang="en-simple" hreflang="en-simple" data-title="Therapeutic index" data-language-autonym="Simple English" data-language-local-name="Simple English" class="interlanguage-link-target"><span>Simple English</span></a></li><li class="interlanguage-link interwiki-sl mw-list-item"><a href="https://sl.wikipedia.org/wiki/Terapevtski_indeks" title="Terapevtski indeks – Slovenian" lang="sl" hreflang="sl" data-title="Terapevtski indeks" data-language-autonym="Slovenščina" data-language-local-name="Slovenian" class="interlanguage-link-target"><span>Slovenščina</span></a></li><li class="interlanguage-link interwiki-sr mw-list-item"><a href="https://sr.wikipedia.org/wiki/Terapeutski_indeks" title="Terapeutski indeks – Serbian" lang="sr" hreflang="sr" data-title="Terapeutski indeks" data-language-autonym="Српски / srpski" data-language-local-name="Serbian" class="interlanguage-link-target"><span>Српски / srpski</span></a></li><li class="interlanguage-link interwiki-sh mw-list-item"><a href="https://sh.wikipedia.org/wiki/Terapeutski_indeks" title="Terapeutski indeks – Serbo-Croatian" lang="sh" hreflang="sh" data-title="Terapeutski indeks" data-language-autonym="Srpskohrvatski / српскохрватски" data-language-local-name="Serbo-Croatian" class="interlanguage-link-target"><span>Srpskohrvatski / српскохрватски</span></a></li><li class="interlanguage-link interwiki-fi mw-list-item"><a href="https://fi.wikipedia.org/wiki/Terapeuttinen_indeksi" title="Terapeuttinen indeksi – Finnish" lang="fi" hreflang="fi" data-title="Terapeuttinen indeksi" data-language-autonym="Suomi" data-language-local-name="Finnish" class="interlanguage-link-target"><span>Suomi</span></a></li><li class="interlanguage-link interwiki-sv mw-list-item"><a href="https://sv.wikipedia.org/wiki/Terapeutiskt_index" title="Terapeutiskt index – Swedish" lang="sv" hreflang="sv" data-title="Terapeutiskt index" data-language-autonym="Svenska" data-language-local-name="Swedish" class="interlanguage-link-target"><span>Svenska</span></a></li><li class="interlanguage-link interwiki-ta mw-list-item"><a href="https://ta.wikipedia.org/wiki/%E0%AE%A8%E0%AF%8B%E0%AE%AF%E0%AF%8D%E0%AE%A8%E0%AF%80%E0%AE%95%E0%AF%8D%E0%AE%95%E0%AE%B2%E0%AF%8D_%E0%AE%95%E0%AF%81%E0%AE%B1%E0%AE%BF%E0%AE%AF%E0%AF%80%E0%AE%9F%E0%AF%8D%E0%AE%9F%E0%AF%86%E0%AE%A3%E0%AF%8D" title="நோய்நீக்கல் குறியீட்டெண் – Tamil" lang="ta" hreflang="ta" data-title="நோய்நீக்கல் குறியீட்டெண்" data-language-autonym="தமிழ்" data-language-local-name="Tamil" class="interlanguage-link-target"><span>தமிழ்</span></a></li><li class="interlanguage-link interwiki-uk mw-list-item"><a href="https://uk.wikipedia.org/wiki/%D0%A2%D0%B5%D1%80%D0%B0%D0%BF%D0%B5%D0%B2%D1%82%D0%B8%D1%87%D0%BD%D0%B8%D0%B9_%D1%96%D0%BD%D0%B4%D0%B5%D0%BA%D1%81" title="Терапевтичний індекс – Ukrainian" lang="uk" hreflang="uk" data-title="Терапевтичний індекс" data-language-autonym="Українська" data-language-local-name="Ukrainian" class="interlanguage-link-target"><span>Українська</span></a></li><li class="interlanguage-link interwiki-zh mw-list-item"><a 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<div class="mw-indicators"> </div> <div id="siteSub" class="noprint">From Wikipedia, the free encyclopedia</div> </div> <div id="contentSub"><div id="mw-content-subtitle"></div></div> <div id="mw-content-text" class="mw-body-content"><div class="mw-content-ltr mw-parser-output" lang="en" dir="ltr"><div class="shortdescription nomobile noexcerpt noprint searchaux" style="display:none">Quantitative measurement of the relative safety of a drug</div> <p>The <b>therapeutic index</b> (<b>TI</b>; also referred to as <b>therapeutic ratio</b>) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the <a href="/wiki/Therapeutic_effect" title="Therapeutic effect">therapeutic effect</a>.<sup id="cite_ref-1" class="reference"><a href="#cite_note-1"><span class="cite-bracket">[</span>1<span class="cite-bracket">]</span></a></sup> The related terms <b>therapeutic window</b> or <b>safety window</b> refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity. </p><p>Classically, for clinical <a href="/wiki/Indication_(medicine)" title="Indication (medicine)">indications</a> of an approved drug, TI refers to the ratio of the <a href="/wiki/Dose_(biochemistry)" title="Dose (biochemistry)">dose</a> of the drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, <a href="/wiki/Median_toxic_dose" title="Median toxic dose">TD<sub>50</sub></a>) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED<sub>50</sub>). In contrast, in a <a href="/wiki/Drug_development" title="Drug development">drug development</a> setting TI is calculated based on plasma <a href="https://en.wiktionary.org/wiki/exposure" class="extiw" title="wikt:exposure">exposure</a> levels.<sup id="cite_ref-muller-Milton2012_2-0" class="reference"><a href="#cite_note-muller-Milton2012-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> </p><p>In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population (<a href="/wiki/LD50" class="mw-redirect" title="LD50">LD<sub>50</sub></a>) divided by the minimum <a href="/wiki/Effective_dose_(pharmacology)" title="Effective dose (pharmacology)">effective dose</a> for 50% of the population (ED<sub>50</sub>). In modern settings, more sophisticated toxicity endpoints are used. </p><p>For many drugs, severe toxicities in humans occur at sublethal doses, which limit their maximum dose. A higher safety-based therapeutic index is preferable instead of a lower one; an individual would have to take a much higher dose of a drug to reach the lethal threshold than the dose taken to induce the therapeutic effect of the drug. However, a lower efficacy-based therapeutic index is preferable instead of a higher one; an individual would have to take a higher dose of a drug to reach the toxic threshold than the dose taken to induce the therapeutic effect of the drug. </p> <style data-mw-deduplicate="TemplateStyles:r1236090951">.mw-parser-output .hatnote{font-style:italic}.mw-parser-output div.hatnote{padding-left:1.6em;margin-bottom:0.5em}.mw-parser-output .hatnote i{font-style:normal}.mw-parser-output .hatnote+link+.hatnote{margin-top:-0.5em}@media print{body.ns-0 .mw-parser-output .hatnote{display:none!important}}</style><div role="note" class="hatnote navigation-not-searchable">For more details about types of therapeutic index, see <a class="mw-selflink-fragment" href="#Types">§ Types</a>.</div> <p>Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of its blood levels in the person taking it. This may be achieved through <a href="/wiki/Therapeutic_drug_monitoring" title="Therapeutic drug monitoring">therapeutic drug monitoring</a> (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with <a href="/wiki/Lithium_(medication)" title="Lithium (medication)">lithium</a> due to its narrow therapeutic range.<sup id="cite_ref-3" class="reference"><a href="#cite_note-3"><span class="cite-bracket">[</span>3<span class="cite-bracket">]</span></a></sup> </p> <table class="wikitable"> <tbody><tr> <th>Term</th> <th>Full form</th> <th>Definition </th></tr> <tr> <td>ED </td> <td>Effective Dose </td> <td>the <a href="/wiki/Dose_(biochemistry)" title="Dose (biochemistry)">dose</a> or <a href="/wiki/Concentration" title="Concentration">concentration</a> of a <a href="/wiki/Medication" title="Medication">drug</a> that produces a biological response.<sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><span class="cite-bracket">[</span>4<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-5" class="reference"><a href="#cite_note-5"><span class="cite-bracket">[</span>5<span class="cite-bracket">]</span></a></sup> </td></tr> <tr> <td>TD </td> <td>Toxic Dose </td> <td>the dose at which <a href="/wiki/Toxicity" title="Toxicity">toxicity</a> occurs in 50% of cases. </td></tr> <tr> <td>LD </td> <td>Lethal Dose </td> <td>the dose at which <a href="/wiki/Death" title="Death">death</a> occurs in 50% of cases.<sup id="cite_ref-Goodman_&_Gilman2011_6-0" class="reference"><a href="#cite_note-Goodman_&_Gilman2011-6"><span class="cite-bracket">[</span>6<span class="cite-bracket">]</span></a></sup><sup class="reference nowrap"><span title="Page / location: 73">: 73 </span></sup><sup id="cite_ref-7" class="reference"><a href="#cite_note-7"><span class="cite-bracket">[</span>7<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-8" class="reference"><a href="#cite_note-8"><span class="cite-bracket">[</span>8<span class="cite-bracket">]</span></a></sup> </td></tr> <tr> <td>TI </td> <td>Therapeutic Index </td> <td>a quantitative measurement of the relative safety of a drug by comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect<sup id="cite_ref-9" class="reference"><a href="#cite_note-9"><span class="cite-bracket">[</span>9<span class="cite-bracket">]</span></a></sup> </td></tr></tbody></table> <meta property="mw:PageProp/toc" /> <div class="mw-heading mw-heading2"><h2 id="Types">Types</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=1" title="Edit section: Types"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Based on <a href="/wiki/Efficacy_(pharmacology)" class="mw-redirect" title="Efficacy (pharmacology)">efficacy</a> and <a href="/wiki/Drug_safety" class="mw-redirect" title="Drug safety">safety</a> of drugs, there are two types of therapeutic index: </p> <dl><dt>Safety-based therapeutic index</dt></dl> <p><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle TI_{\text{safety}}={\frac {LD_{50}}{ED_{50}}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>safety</mtext> </mrow> </msub> <mo>=</mo> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mrow> <mi>L</mi> <msub> <mi>D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>50</mn> </mrow> </msub> </mrow> <mrow> <mi>E</mi> <msub> <mi>D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>50</mn> </mrow> </msub> </mrow> </mfrac> </mrow> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle TI_{\text{safety}}={\frac {LD_{50}}{ED_{50}}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/2a6aadc0d27e93090fb0150e4bc276984250d2c7" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -2.338ex; width:16.613ex; height:5.843ex;" alt="{\displaystyle TI_{\text{safety}}={\frac {LD_{50}}{ED_{50}}}}"></span> It is desirous for the value of LD<sub>50</sub> to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TI<sub>safety</sub> increases as the difference between LD<sub>50</sub> and ED<sub>50</sub> increases—hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vise-versa. </p> <dl><dt>Efficacy-based therapeutic index</dt></dl> <p><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle TI_{\text{efficacy}}={\frac {ED_{50}}{TD_{50}}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>efficacy</mtext> </mrow> </msub> <mo>=</mo> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mrow> <mi>E</mi> <msub> <mi>D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>50</mn> </mrow> </msub> </mrow> <mrow> <mi>T</mi> <msub> <mi>D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>50</mn> </mrow> </msub> </mrow> </mfrac> </mrow> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle TI_{\text{efficacy}}={\frac {ED_{50}}{TD_{50}}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/d8b65dd482b8a79307dd2b762ba86816b40a528b" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -2.338ex; width:17.746ex; height:5.843ex;" alt="{\displaystyle TI_{\text{efficacy}}={\frac {ED_{50}}{TD_{50}}}}"></span> Ideally the ED<sub>50</sub> is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD<sub>50</sub> is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED<sub>50</sub> and TD<sub>50</sub>, the greater the value of TI<sub>efficacy</sub>. Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window. </p> <dl><dt>Protective index</dt></dl> <p>Similar to safety-based therapeutic index, the <a href="/wiki/Protective_index" title="Protective index">protective index</a> uses TD<sub>50</sub> (median <i>toxic</i> dose) in place of LD<sub>50</sub>. </p><p><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle {\text{Protective index}}={\frac {TD_{50}}{ED_{50}}}={\frac {1}{TI_{\text{efficacy}}}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mrow class="MJX-TeXAtom-ORD"> <mtext>Protective index</mtext> </mrow> <mo>=</mo> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mrow> <mi>T</mi> <msub> <mi>D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>50</mn> </mrow> </msub> </mrow> <mrow> <mi>E</mi> <msub> <mi>D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>50</mn> </mrow> </msub> </mrow> </mfrac> </mrow> <mo>=</mo> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mn>1</mn> <mrow> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>efficacy</mtext> </mrow> </msub> </mrow> </mfrac> </mrow> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle {\text{Protective index}}={\frac {TD_{50}}{ED_{50}}}={\frac {1}{TI_{\text{efficacy}}}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/d6cb711b98149d0b61f174a0230f04a0a5a5e01e" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -2.505ex; width:38.191ex; height:6.009ex;" alt="{\displaystyle {\text{Protective index}}={\frac {TD_{50}}{ED_{50}}}={\frac {1}{TI_{\text{efficacy}}}}}"></span> </p><p>For many substances, toxicity can occur at levels far below lethal effects (that cause death), and thus, if toxicity is properly specified, the protective index is often more informative about a substance's relative safety. Nevertheless, the safety-based therapeutic index (<span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle {TI_{\text{safety}}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mrow class="MJX-TeXAtom-ORD"> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>safety</mtext> </mrow> </msub> </mrow> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle {TI_{\text{safety}}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/d9229d2fbe4e940fd7356c332516cb1000a36ef0" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -1.005ex; width:7.103ex; height:2.843ex;" alt="{\displaystyle {TI_{\text{safety}}}}"></span>) is still useful as it can be considered an <a href="/wiki/Upper_bound" class="mw-redirect" title="Upper bound">upper bound</a> of the protective index, and the former also has the advantages of objectivity and easier comprehension. </p><p>Since the protective index (PI) is calculated as TD<sub>50</sub> divided by ED<sub>50</sub>, it can be mathematically expressed that: </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle TI_{\text{efficacy}}={\frac {1}{\text{Protective index}}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>efficacy</mtext> </mrow> </msub> <mo>=</mo> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mn>1</mn> <mtext>Protective index</mtext> </mfrac> </mrow> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle TI_{\text{efficacy}}={\frac {1}{\text{Protective index}}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/2c1e03f72ae781dfb18005f335a56c8d81fada1e" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -2.005ex; width:28.68ex; height:5.343ex;" alt="{\displaystyle TI_{\text{efficacy}}={\frac {1}{\text{Protective index}}}}"></span></dd></dl> <p>which means that <span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle TI_{\text{efficacy}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>efficacy</mtext> </mrow> </msub> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle TI_{\text{efficacy}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/c6fea19a230ccfc34a52dff584f11efd0dfdf590" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -1.005ex; width:8.236ex; height:2.843ex;" alt="{\displaystyle TI_{\text{efficacy}}}"></span> is a <a href="/wiki/Multiplicative_inverse" title="Multiplicative inverse">reciprocal</a> of protective index. </p><p>All the above types of therapeutic index can be used in both <a href="/wiki/Pre-clinical_trial" class="mw-redirect" title="Pre-clinical trial">pre-clinical trials</a> and <a href="/wiki/Clinical_trial" title="Clinical trial">clinical trials</a>. </p> <div class="mw-heading mw-heading2"><h2 id="Drug_development">Drug development</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=2" title="Edit section: Drug development"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>A low efficacy-based therapeutic index (<span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle TI_{\text{efficacy}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>efficacy</mtext> </mrow> </msub> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle TI_{\text{efficacy}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/c6fea19a230ccfc34a52dff584f11efd0dfdf590" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -1.005ex; width:8.236ex; height:2.843ex;" alt="{\displaystyle TI_{\text{efficacy}}}"></span>) and a high safety-based therapeutic index (<span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle TI_{\text{safety}}}"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mi>T</mi> <msub> <mi>I</mi> <mrow class="MJX-TeXAtom-ORD"> <mtext>safety</mtext> </mrow> </msub> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle TI_{\text{safety}}}</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/72c34fdee661ac358f2102bc450ff91c4088a27a" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -1.005ex; width:7.103ex; height:2.843ex;" alt="{\displaystyle TI_{\text{safety}}}"></span>) are preferable for a drug to have a favorable efficacy vs safety profile. At the early discovery/development stage, the clinical TI of a drug candidate is unknown. However, understanding the preliminary TI of a drug candidate is of utmost importance as early as possible since TI is an important indicator of the probability of successful development. Recognizing drug candidates with potentially suboptimal TI at the earliest possible stage helps to initiate mitigation or potentially re-deploy resources. </p><p>TI is the quantitative relationship between pharmacological efficacy and toxicological safety of a drug, without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI into something useful, the nature and limitations of pharmacological and/or toxicological endpoints must be considered. Depending on the intended clinical indication, the associated unmet medical need and/or the competitive situation, more or less weight can be given to either the safety or efficacy of a drug candidate in order to create a well balanced indication-specific efficacy vs safety profile. </p><p>In general, it is the exposure of a given tissue to drug (i.e. drug concentration over time), rather than dose, that drives the pharmacological and toxicological effects. For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors. These considerations emphasize the importance of using exposure instead of dose to calculate TI. To account for delays between exposure and toxicity, the TI for toxicities that occur after multiple dose administrations should be calculated using the exposure to drug at steady state rather than after administration of a single dose. </p><p>A review published by Muller and Milton in <i><a href="/wiki/Nature_Reviews_Drug_Discovery" title="Nature Reviews Drug Discovery">Nature Reviews Drug Discovery</a></i> critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.<sup id="cite_ref-muller-Milton2012_2-1" class="reference"><a href="#cite_note-muller-Milton2012-2"><span class="cite-bracket">[</span>2<span class="cite-bracket">]</span></a></sup> </p> <div class="mw-heading mw-heading2"><h2 id="Range_of_therapeutic_indices">Range of therapeutic indices</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=3" title="Edit section: Range of therapeutic indices"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The therapeutic index varies widely among substances, even within a related group. </p><p>For instance, the <a href="/wiki/Opioid" title="Opioid">opioid</a> <a href="/wiki/Analgesics" class="mw-redirect" title="Analgesics">painkiller</a> <a href="/wiki/Remifentanil" title="Remifentanil">remifentanil</a> is very forgiving, offering a therapeutic index of 33,000:1, while <a href="/wiki/Diazepam" title="Diazepam">Diazepam</a>, a <a href="/wiki/Benzodiazepine" title="Benzodiazepine">benzodiazepine</a> <a href="/wiki/Sedative-hypnotic" class="mw-redirect" title="Sedative-hypnotic">sedative-hypnotic</a> and skeletal <a href="/wiki/Muscle_relaxant" title="Muscle relaxant">muscle relaxant</a>, has a less forgiving therapeutic index of 100:1.<sup id="cite_ref-10" class="reference"><a href="#cite_note-10"><span class="cite-bracket">[</span>10<span class="cite-bracket">]</span></a></sup> Morphine is even less so with a therapeutic index of 70. </p><p>Less safe are <a href="/wiki/Cocaine" title="Cocaine">cocaine</a> (a <a href="/wiki/Stimulant" title="Stimulant">stimulant</a> and <a href="/wiki/Local_anaesthetic" class="mw-redirect" title="Local anaesthetic">local anaesthetic</a>) and <a href="/wiki/Ethanol" title="Ethanol">ethanol</a> (colloquially, the "alcohol" in <a href="/wiki/Alcoholic_beverage" title="Alcoholic beverage">alcoholic beverages</a>, a widely available <a href="/wiki/Sedative" title="Sedative">sedative</a> consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively.<sup id="cite_ref-Drug_comparison_11-0" class="reference"><a href="#cite_note-Drug_comparison-11"><span class="cite-bracket">[</span>11<span class="cite-bracket">]</span></a></sup> <a href="/wiki/Paracetamol" title="Paracetamol">Paracetamol</a>, alternatively known by its trade names <a href="/wiki/Tylenol_(brand)" title="Tylenol (brand)">Tylenol</a> or Panadol, also has a therapeutic index of 10.<sup id="cite_ref-12" class="reference"><a href="#cite_note-12"><span class="cite-bracket">[</span>12<span class="cite-bracket">]</span></a></sup> </p><p>Even less safe are drugs such as <a href="/wiki/Digoxin" title="Digoxin">digoxin</a>, a <a href="/wiki/Cardiac_glycoside" title="Cardiac glycoside">cardiac glycoside</a>; its therapeutic index is approximately 2:1.<sup id="cite_ref-13" class="reference"><a href="#cite_note-13"><span class="cite-bracket">[</span>13<span class="cite-bracket">]</span></a></sup> </p><p>Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include <a href="/wiki/Dimercaprol" title="Dimercaprol">dimercaprol</a>, <a href="/wiki/Theophylline" title="Theophylline">theophylline</a>, <a href="/wiki/Warfarin" title="Warfarin">warfarin</a> and <a href="/wiki/Lithium_carbonate" title="Lithium carbonate">lithium carbonate</a>. </p><p>Some antibiotics and antifungals require monitoring to balance efficacy with minimizing <a href="/wiki/Adverse_effect" title="Adverse effect">adverse effects</a>, including: <a href="/wiki/Gentamicin" title="Gentamicin">gentamicin</a>, <a href="/wiki/Vancomycin" title="Vancomycin">vancomycin</a>, <a href="/wiki/Amphotericin_B" title="Amphotericin B">amphotericin B</a> (nicknamed 'amphoterrible' for this very reason), and <a href="/wiki/Polymyxin_B" title="Polymyxin B">polymyxin B</a>. </p> <div class="mw-heading mw-heading3"><h3 id="Cancer_radiotherapy">Cancer radiotherapy</h3><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=4" title="Edit section: Cancer radiotherapy"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from <a href="/wiki/X-ray" title="X-ray">x-rays</a>, <a href="/wiki/Gamma_ray" title="Gamma ray">gamma rays</a>, or <a href="/wiki/Charged_particle" title="Charged particle">charged</a> or heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is determined by the maximum radiation dose for killing cancer cells and the minimum radiation dose causing acute or late morbidity in cells of normal tissues.<sup id="cite_ref-Thoms_217–222_14-0" class="reference"><a href="#cite_note-Thoms_217–222-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup> Both of these parameters have <a href="/wiki/Sigmoid_function" title="Sigmoid function">sigmoidal</a> <a href="/wiki/Dose%E2%80%93response_curve" class="mw-redirect" title="Dose–response curve">dose–response curves</a>. Thus, a favorable outcome in dose–response for tumor tissue is greater than that of normal tissue for the same dose, meaning that the treatment is effective on tumors and does not cause serious morbidity to normal tissue. Conversely, overlapping response for two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment of tumors. The mechanism of radiation therapy is categorized as direct or indirect radiation. Both direct and indirect radiation induce <a href="/wiki/DNA_mutation" class="mw-redirect" title="DNA mutation">DNA mutation</a> or <a href="/wiki/Chromosomal_rearrangement" title="Chromosomal rearrangement">chromosomal rearrangement</a> during its repair process. Direct radiation creates a DNA <a href="/wiki/Free_radical" class="mw-redirect" title="Free radical">free radical</a> from radiation energy deposition that damages DNA. Indirect radiation occurs from <a href="/wiki/Radiolysis" title="Radiolysis">radiolysis</a> of water, creating a free <a href="/wiki/Hydroxyl_radical" title="Hydroxyl radical">hydroxyl radical</a>, <a href="/wiki/Hydronium" title="Hydronium">hydronium</a> and electron. The hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage the base region of DNA.<sup id="cite_ref-15" class="reference"><a href="#cite_note-15"><span class="cite-bracket">[</span>15<span class="cite-bracket">]</span></a></sup> </p><p>Cancer cells cause an imbalance of signals in the <a href="/wiki/Cell_cycle" title="Cell cycle">cell cycle</a>. G1 and G2/M arrest were found to be major checkpoints by irradiating human cells. G1 arrest delays the repair mechanism before synthesis of DNA in <a href="/wiki/S_phase" title="S phase">S phase</a> and <a href="/wiki/Mitosis" title="Mitosis">mitosis</a> in M phase, suggesting it is a key checkpoint for survival of cells. G2/M arrest occurs when cells need to repair after S phase but before mitotic entry. It is known that S phase is the most resistant to radiation and M phase is the most sensitive to radiation. <a href="/wiki/P53" title="P53">p53</a>, a tumor suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle through radiation. For example, irradiation of <a href="/wiki/Myeloid_leukemia" title="Myeloid leukemia">myeloid leukemia</a> cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with <a href="/wiki/Ataxia_telangiectasia" class="mw-redirect" title="Ataxia telangiectasia">Ataxia telangiectasia</a> delays have hypersensitivity to radiation due to the delay of accumulation of p53.<sup id="cite_ref-16" class="reference"><a href="#cite_note-16"><span class="cite-bracket">[</span>16<span class="cite-bracket">]</span></a></sup> In this case, cells are able to replicate without repair of their DNA, becoming prone to incidence of cancer. Most cells are in G1 and S phase. Irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been a focus for therapeutic treatment. Irradiation of a tissue induces a response in both irradiated and non-irridiated cells. It was found that even cells up to 50–75 cell diameters distant from irradiated cells exhibit a <a href="/wiki/Phenotype" title="Phenotype">phenotype</a> of enhanced genetic instability such as micronucleation.<sup id="cite_ref-17" class="reference"><a href="#cite_note-17"><span class="cite-bracket">[</span>17<span class="cite-bracket">]</span></a></sup> This suggests an effect on cell-to-cell communication such as <a href="/wiki/Paracrine" class="mw-redirect" title="Paracrine">paracrine</a> and <a href="/wiki/Juxtacrine_signaling" class="mw-redirect" title="Juxtacrine signaling">juxtacrine signaling</a>. Normal cells do not lose their <a href="/wiki/DNA_repair" title="DNA repair">DNA repair</a> mechanism whereas cancer cells often lose it during radiotherapy. However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of <a href="/wiki/Carcinogenesis" title="Carcinogenesis">carcinogenesis</a>. This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation. Molecular targeting of the DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA <a href="/wiki/Double-strand_break" class="mw-redirect" title="Double-strand break">double-strand breaks</a>. Direct inhibitors target proteins (<a href="/wiki/Poly_ADP_ribose_polymerase" class="mw-redirect" title="Poly ADP ribose polymerase">PARP family</a>) and <a href="/wiki/Kinases" class="mw-redirect" title="Kinases">kinases</a> (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as <a href="/wiki/Epidermal_growth_factor_receptor" title="Epidermal growth factor receptor">EGFR</a> and <a href="/wiki/Insulin_growth_factor" class="mw-redirect" title="Insulin growth factor">insulin growth factor</a>.<sup id="cite_ref-Thoms_217–222_14-1" class="reference"><a href="#cite_note-Thoms_217–222-14"><span class="cite-bracket">[</span>14<span class="cite-bracket">]</span></a></sup> </p><p>The effective therapeutic index can be affected by <a href="/wiki/Targeted_drug_delivery" title="Targeted drug delivery">targeting</a>, in which the therapeutic agent is concentrated in its desirable area of effect. For example, in <a href="/wiki/Radiation_treatment" class="mw-redirect" title="Radiation treatment">radiation therapy</a> for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as in <a href="/wiki/Peptide_receptor_radionuclide_therapy" title="Peptide receptor radionuclide therapy">peptide receptor radionuclide therapy</a> for <a href="/wiki/Neuroendocrine_tumors" class="mw-redirect" title="Neuroendocrine tumors">neuroendocrine tumors</a> and in <a href="/wiki/Chemoembolization" class="mw-redirect" title="Chemoembolization">chemoembolization</a> or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity. </p> <div class="mw-heading mw-heading2"><h2 id="Safety_ratio">Safety ratio</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=5" title="Edit section: Safety ratio"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Sometimes the term <b>safety ratio</b> is used, particularly when referring to <a href="/wiki/Psychoactive_drugs" class="mw-redirect" title="Psychoactive drugs">psychoactive drugs</a> used for non-therapeutic purposes, e.g. recreational use.<sup id="cite_ref-Drug_comparison_11-1" class="reference"><a href="#cite_note-Drug_comparison-11"><span class="cite-bracket">[</span>11<span class="cite-bracket">]</span></a></sup> In such cases, the <i>effective</i> dose is the amount and frequency that produces the <i>desired</i> effect, which can vary, and can be greater or less than the therapeutically effective dose. </p><p>The <i>Certain Safety Factor</i>, also referred to as the <i>Margin of Safety (MOS)</i>, is the ratio of the <a href="/wiki/Lethal_dose" title="Lethal dose">lethal dose</a> to 1% of population to the <a href="/wiki/Effective_dose_(pharmacology)" title="Effective dose (pharmacology)">effective dose</a> to 99% of the population (LD<sub>1</sub>/ED<sub>99</sub>).<sup id="cite_ref-18" class="reference"><a href="#cite_note-18"><span class="cite-bracket">[</span>18<span class="cite-bracket">]</span></a></sup> This is a better safety index than the <a href="/wiki/Median_lethal_dose" title="Median lethal dose">LD<sub>50</sub></a> for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another. </p> <dl><dd><span class="mwe-math-element"><span class="mwe-math-mathml-inline mwe-math-mathml-a11y" style="display: none;"><math xmlns="http://www.w3.org/1998/Math/MathML" alttext="{\displaystyle {\text{Certain safety factor}}=\mathrm {\frac {LD_{1}}{ED_{99}}} }"> <semantics> <mrow class="MJX-TeXAtom-ORD"> <mstyle displaystyle="true" scriptlevel="0"> <mrow class="MJX-TeXAtom-ORD"> <mtext>Certain safety factor</mtext> </mrow> <mo>=</mo> <mrow class="MJX-TeXAtom-ORD"> <mfrac> <mrow> <mi mathvariant="normal">L</mi> <msub> <mi mathvariant="normal">D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>1</mn> </mrow> </msub> </mrow> <mrow> <mi mathvariant="normal">E</mi> <msub> <mi mathvariant="normal">D</mi> <mrow class="MJX-TeXAtom-ORD"> <mn>99</mn> </mrow> </msub> </mrow> </mfrac> </mrow> </mstyle> </mrow> <annotation encoding="application/x-tex">{\displaystyle {\text{Certain safety factor}}=\mathrm {\frac {LD_{1}}{ED_{99}}} }</annotation> </semantics> </math></span><img src="https://wikimedia.org/api/rest_v1/media/math/render/svg/252ee7e128205fe78a5d6b6bdfa8f7265375ae92" class="mwe-math-fallback-image-inline mw-invert skin-invert" aria-hidden="true" style="vertical-align: -2.338ex; width:29.8ex; height:5.676ex;" alt="{\displaystyle {\text{Certain safety factor}}=\mathrm {\frac {LD_{1}}{ED_{99}}} }"></span></dd></dl> <div class="mw-heading mw-heading2"><h2 id="Synergistic_effect">Synergistic effect</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=6" title="Edit section: Synergistic effect"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>A therapeutic index does not consider drug interactions or <a href="/wiki/Synergy" title="Synergy">synergistic</a> effects. For example, the risk associated with <a href="/wiki/Benzodiazepine" title="Benzodiazepine">benzodiazepines</a> increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone.<sup class="noprint Inline-Template Template-Fact" style="white-space:nowrap;">[<i><a href="/wiki/Wikipedia:Identifying_reliable_sources_(medicine)" title="Wikipedia:Identifying reliable sources (medicine)"><span title="Material near this tag needs references to reliable medical sources. (September 2013)">medical citation needed</span></a></i>]</sup> Therapeutic index also does not take into account the ease or difficulty of reaching a toxic or lethal dose. This is more of a consideration for recreational drug users, as the purity can be highly variable. </p> <div class="mw-heading mw-heading2"><h2 id="Therapeutic_window">Therapeutic window</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=7" title="Edit section: Therapeutic window"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The <i>therapeutic window</i> (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects.<sup id="cite_ref-19" class="reference"><a href="#cite_note-19"><span class="cite-bracket">[</span>19<span class="cite-bracket">]</span></a></sup> Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include <a href="/wiki/Theophylline" title="Theophylline">theophylline</a>, <a href="/wiki/Digoxin" title="Digoxin">digoxin</a>, <a href="/wiki/Lithium_(medication)" title="Lithium (medication)">lithium</a>, and <a href="/wiki/Warfarin" title="Warfarin">warfarin</a>. </p> <div class="mw-heading mw-heading2"><h2 id="Optimal_biological_dose">Optimal biological dose</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=8" title="Edit section: Optimal biological dose"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>Optimal biological dose (OBD) is the quantity of a drug that will most effectively produce the desired effect while remaining in the range of acceptable toxicity. </p> <div class="mw-heading mw-heading2"><h2 id="Maximum_tolerated_dose">Maximum tolerated dose</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=9" title="Edit section: Maximum tolerated dose"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <p>The <b>maximum tolerated dose</b> (MTD) refers to the highest dose of a radiological or <a href="/wiki/Pharmacological_agent" class="mw-redirect" title="Pharmacological agent">pharmacological</a> treatment that will produce the desired effect without unacceptable <a href="/wiki/Toxicity" title="Toxicity">toxicity</a>.<sup id="cite_ref-20" class="reference"><a href="#cite_note-20"><span class="cite-bracket">[</span>20<span class="cite-bracket">]</span></a></sup><sup id="cite_ref-21" class="reference"><a href="#cite_note-21"><span class="cite-bracket">[</span>21<span class="cite-bracket">]</span></a></sup> The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable <a href="/wiki/Adverse_health_effect" class="mw-redirect" title="Adverse health effect">adverse health effects</a> in a population, when the level of exposure is not sufficient to cause premature <a href="/wiki/Mortality_rate" title="Mortality rate">mortality</a> due to short-term <a href="/wiki/Toxic_effect" class="mw-redirect" title="Toxic effect">toxic effects</a>. The maximum dose is used, rather than a lower dose, to reduce the number of <a href="/wiki/Human_subjects_research" class="mw-redirect" title="Human subjects research">test subjects</a> (and, among other things, the cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing <a href="/wiki/Chemical_residue" class="mw-redirect" title="Chemical residue">chemical residue</a> tolerances in foods. Maximum tolerated dose studies are also done in <a href="/wiki/Clinical_trials" class="mw-redirect" title="Clinical trials">clinical trials</a>. </p><p>MTD is an essential aspect of a drug's profile. All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent the prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population. </p><p>Patients are often unable to tolerate the theoretical MTD of a drug due to the occurrence of side-effects which are not innately a manifestation of toxicity (not considered to severely threaten a patient's health) but cause the patient sufficient distress and/or discomfort to result in non-compliance with treatment. Such examples include emotional "blunting" with antidepressants, <a href="/wiki/Pruritus" class="mw-redirect" title="Pruritus">pruritus</a> with <a href="/wiki/Opiates" class="mw-redirect" title="Opiates">opiates</a>, and blurred vision with <a href="/wiki/Anticholinergics" class="mw-redirect" title="Anticholinergics">anticholinergics</a>. </p> <div class="mw-heading mw-heading2"><h2 id="See_also">See also</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=10" title="Edit section: See also"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <ul><li><a href="/wiki/Drug_titration" title="Drug titration">Drug titration</a> – process of finding the correct dose of a drug</li> <li><a href="/wiki/Effective_dose_(pharmacology)" title="Effective dose (pharmacology)">Effective dose</a></li> <li><a href="/wiki/EC50" title="EC50">EC50</a></li> <li><a href="/wiki/IC50" title="IC50">IC50</a></li> <li><a href="/wiki/LD50" class="mw-redirect" title="LD50">LD50</a></li> <li><a href="/wiki/Hormesis" title="Hormesis">Hormesis</a></li></ul> <div class="mw-heading mw-heading2"><h2 id="References">References</h2><span class="mw-editsection"><span class="mw-editsection-bracket">[</span><a href="/w/index.php?title=Therapeutic_index&action=edit&section=11" title="Edit section: References"><span>edit</span></a><span class="mw-editsection-bracket">]</span></span></div> <style data-mw-deduplicate="TemplateStyles:r1239543626">.mw-parser-output .reflist{margin-bottom:0.5em;list-style-type:decimal}@media screen{.mw-parser-output .reflist{font-size:90%}}.mw-parser-output .reflist .references{font-size:100%;margin-bottom:0;list-style-type:inherit}.mw-parser-output .reflist-columns-2{column-width:30em}.mw-parser-output .reflist-columns-3{column-width:25em}.mw-parser-output .reflist-columns{margin-top:0.3em}.mw-parser-output .reflist-columns ol{margin-top:0}.mw-parser-output .reflist-columns li{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .reflist-upper-alpha{list-style-type:upper-alpha}.mw-parser-output .reflist-upper-roman{list-style-type:upper-roman}.mw-parser-output .reflist-lower-alpha{list-style-type:lower-alpha}.mw-parser-output .reflist-lower-greek{list-style-type:lower-greek}.mw-parser-output .reflist-lower-roman{list-style-type:lower-roman}</style><div class="reflist reflist-columns references-column-width" style="column-width: 33em;"> <ol class="references"> <li id="cite_note-1"><span class="mw-cite-backlink"><b><a href="#cite_ref-1">^</a></b></span> <span class="reference-text"><style data-mw-deduplicate="TemplateStyles:r1238218222">.mw-parser-output cite.citation{font-style:inherit;word-wrap:break-word}.mw-parser-output .citation q{quotes:"\"""\"""'""'"}.mw-parser-output .citation:target{background-color:rgba(0,127,255,0.133)}.mw-parser-output .id-lock-free.id-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/6/65/Lock-green.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-limited.id-lock-limited a,.mw-parser-output .id-lock-registration.id-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/d/d6/Lock-gray-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .id-lock-subscription.id-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/a/aa/Lock-red-alt-2.svg")right 0.1em center/9px no-repeat}.mw-parser-output .cs1-ws-icon a{background:url("//upload.wikimedia.org/wikipedia/commons/4/4c/Wikisource-logo.svg")right 0.1em center/12px no-repeat}body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-free a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-limited a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-registration a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .id-lock-subscription a,body:not(.skin-timeless):not(.skin-minerva) .mw-parser-output .cs1-ws-icon a{background-size:contain;padding:0 1em 0 0}.mw-parser-output .cs1-code{color:inherit;background:inherit;border:none;padding:inherit}.mw-parser-output .cs1-hidden-error{display:none;color:var(--color-error,#d33)}.mw-parser-output .cs1-visible-error{color:var(--color-error,#d33)}.mw-parser-output .cs1-maint{display:none;color:#085;margin-left:0.3em}.mw-parser-output .cs1-kern-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right{padding-right:0.2em}.mw-parser-output .citation .mw-selflink{font-weight:inherit}@media screen{.mw-parser-output .cs1-format{font-size:95%}html.skin-theme-clientpref-night .mw-parser-output .cs1-maint{color:#18911f}}@media screen and (prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output .cs1-maint{color:#18911f}}</style><cite id="CITEREFTrevorKatzungMastersKnuidering-Hall2013" class="citation book cs1">Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). 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incorporates <a href="/wiki/Copyright_status_of_works_by_the_federal_government_of_the_United_States" title="Copyright status of works by the federal government of the United States">public domain material</a> from <link rel="mw-deduplicated-inline-style" href="mw-data:TemplateStyles:r1238218222"><cite id="CITEREFJasper_Womach" class="citation cs1">Jasper Womach. <a rel="nofollow" class="external text" href="http://ncseonline.org/nle/crsreports/05jun/97-905.pdf"><i>Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition</i></a> <span class="cs1-format">(PDF)</span>. <a href="/wiki/Congressional_Research_Service" title="Congressional Research Service">Congressional Research Service</a>.</cite><span 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.navbar a>abbr{text-decoration:inherit}.mw-parser-output .navbar-mini abbr{font-variant:small-caps;border-bottom:none;text-decoration:none;cursor:inherit}.mw-parser-output .navbar-ct-full{font-size:114%;margin:0 7em}.mw-parser-output .navbar-ct-mini{font-size:114%;margin:0 4em}html.skin-theme-clientpref-night .mw-parser-output .navbar li a abbr{color:var(--color-base)!important}@media(prefers-color-scheme:dark){html.skin-theme-clientpref-os .mw-parser-output .navbar li a abbr{color:var(--color-base)!important}}@media print{.mw-parser-output .navbar{display:none!important}}</style><div class="navbar plainlinks hlist navbar-mini"><ul><li class="nv-view"><a href="/wiki/Template:Pharmacology" title="Template:Pharmacology"><abbr title="View this template">v</abbr></a></li><li class="nv-talk"><a href="/wiki/Template_talk:Pharmacology" title="Template talk:Pharmacology"><abbr title="Discuss this template">t</abbr></a></li><li class="nv-edit"><a href="/wiki/Special:EditPage/Template:Pharmacology" title="Special:EditPage/Template:Pharmacology"><abbr title="Edit this template">e</abbr></a></li></ul></div><div id="Pharmacology" style="font-size:114%;margin:0 4em"><a href="/wiki/Pharmacology" title="Pharmacology">Pharmacology</a></div></th></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Ligand_(biochemistry)" title="Ligand (biochemistry)">Ligand (biochemistry)</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Excitatory" scope="row" class="navbox-group" style="width:1%;text-align: center;">Excitatory</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Agonist" title="Agonist">Agonist</a></li> <li><a href="/wiki/Endogenous_agonist" title="Endogenous agonist">Endogenous agonist</a></li> <li><a href="/wiki/Irreversible_agonist" title="Irreversible agonist">Irreversible agonist</a></li> <li><a href="/wiki/Partial_agonist" title="Partial agonist">Partial agonist</a></li> <li><a href="/wiki/Superagonist" title="Superagonist">Superagonist</a></li> <li><a href="/wiki/Physiological_agonism_and_antagonism" title="Physiological agonism and antagonism">Physiological agonist</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Inhibitory" scope="row" class="navbox-group" style="width:1%;text-align: center;">Inhibitory</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Receptor_antagonist" title="Receptor antagonist">Antagonist</a></li> <li><a href="/wiki/Competitive_antagonist" class="mw-redirect" title="Competitive antagonist">Competitive antagonist</a></li> <li><a href="/wiki/Irreversible_antagonist" title="Irreversible antagonist">Irreversible antagonist</a></li> <li><a href="/wiki/Physiological_agonism_and_antagonism" title="Physiological agonism and antagonism">Physiological antagonist</a></li> <li><a href="/wiki/Inverse_agonist" title="Inverse agonist">Inverse agonist</a></li> <li><a href="/wiki/Enzyme_inhibitor" title="Enzyme inhibitor">Enzyme inhibitor</a></li></ul> </div></td></tr></tbody></table><div> <ul><li><a href="/wiki/Drug" title="Drug">Drug</a></li> <li><a href="/wiki/Neurotransmitter" title="Neurotransmitter">Neurotransmitter</a></li> <li><a href="/wiki/Agonist-antagonist" title="Agonist-antagonist">Agonist-antagonist</a></li> <li><a href="/wiki/Pharmacophore" title="Pharmacophore">Pharmacophore</a></li></ul></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Pharmacodynamics" title="Pharmacodynamics">Pharmacodynamics</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Activity_at_receptor" scope="row" class="navbox-group" style="width:1%;text-align: center;">Activity at receptor</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <li><a href="/wiki/Mechanism_of_action" title="Mechanism of action">Mechanism of action</a></li> <li><a href="/wiki/Mode_of_action" title="Mode of action">Mode of action</a></li> <li><a href="/wiki/Molecular_binding" title="Molecular binding">Binding</a></li> <li><a href="/wiki/Receptor_(biochemistry)" title="Receptor (biochemistry)">Receptor (biochemistry)</a></li> <li><a href="/wiki/Desensitization_(medicine)" title="Desensitization (medicine)">Desensitization (medicine)</a></li> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Other_effects_of_ligand" scope="row" class="navbox-group" style="width:1%;text-align: center;">Other effects of ligand</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li>Selectivity (<a href="/wiki/Binding_selectivity" title="Binding selectivity">Binding</a>, <a href="/wiki/Functional_selectivity" title="Functional selectivity">Functional</a>)</li> <li><a href="/wiki/Pleiotropy_(drugs)" title="Pleiotropy (drugs)">Pleiotropy (drugs)</a></li> <li><a href="/wiki/Non-specific_effect_of_vaccines" title="Non-specific effect of vaccines">Non-specific effect of vaccines</a></li> <li><a href="/wiki/Adverse_effect" title="Adverse effect">Adverse effect</a></li> <li><a href="/wiki/Toxicity" title="Toxicity">Toxicity</a> (<a href="/wiki/Neurotoxicity" title="Neurotoxicity">Neurotoxicity</a>)</li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Analysis" scope="row" class="navbox-group" style="width:1%;text-align: center;">Analysis</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Dose%E2%80%93response_relationship" title="Dose–response relationship">Dose–response relationship</a></li> <li><a href="/wiki/Hill_equation_(biochemistry)" title="Hill equation (biochemistry)">Hill equation (biochemistry)</a></li> <li><a href="/wiki/Schild_plot" class="mw-redirect" title="Schild plot">Schild plot</a></li> <li><a href="/wiki/Del_Castillo_Katz_model" class="mw-redirect" title="Del Castillo Katz model">Del Castillo Katz model</a></li> <li><a href="/wiki/Cheng-Prussoff_Equation" class="mw-redirect" title="Cheng-Prussoff Equation">Cheng-Prussoff Equation</a></li> <li>Methods (<a href="/wiki/Organ_bath" title="Organ bath">Organ bath</a>, <a href="/wiki/Ligand_binding_assay" title="Ligand binding assay">Ligand binding assay</a>, <a href="/wiki/Patch_clamp" title="Patch clamp">Patch clamp</a>)</li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Metrics" scope="row" class="navbox-group" style="width:1%;text-align: center;">Metrics</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Efficacy#Pharmacology" title="Efficacy">Efficacy</a></li> <li><a href="/wiki/Intrinsic_activity" title="Intrinsic activity">Intrinsic activity</a></li> <li><a href="/wiki/Potency_(pharmacology)" title="Potency (pharmacology)">Potency</a> (<a href="/wiki/EC50" title="EC50">EC50</a>, <a href="/wiki/IC50" title="IC50">IC50</a>, <a href="/wiki/Effective_dose_(pharmacology)" title="Effective dose (pharmacology)">ED50</a>, <a href="/wiki/Median_lethal_dose" title="Median lethal dose">LD50</a>, <a href="/wiki/Median_toxic_dose" title="Median toxic dose">TD50</a>)</li> <li><a class="mw-selflink selflink">Therapeutic index</a></li> <li><a href="/wiki/Dissociation_constant#Protein-ligand_binding" title="Dissociation constant">Affinity</a></li></ul> </div></td></tr></tbody></table><div></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetics</a></th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Metrics" scope="row" class="navbox-group" style="width:1%;text-align: center;">Metrics</th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Loading_dose" title="Loading dose">Loading dose</a></li> <li><a href="/wiki/Volume_of_distribution" title="Volume of distribution">Volume of distribution</a> (<a href="/wiki/Initial_volume_of_distribution" title="Initial volume of distribution">Initial</a>)</li> <li><a href="/wiki/Rate_of_infusion" title="Rate of infusion">Rate of infusion</a></li> <li><a href="/wiki/Onset_of_action" title="Onset of action">Onset of action</a></li> <li><a href="/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></li> <li><a href="/wiki/Plasma_protein_binding" title="Plasma protein binding">Plasma protein binding</a></li> <li><a href="/wiki/Bioavailability" title="Bioavailability">Bioavailability</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="LADME" scope="row" class="navbox-group" style="width:1%;text-align: center;">LADME</th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/ADME" title="ADME">(L)ADME</a>: (<a href="/wiki/Liberation_(pharmacology)" title="Liberation (pharmacology)">Liberation</a>)</li> <li><a href="/wiki/Absorption_(pharmacology)" title="Absorption (pharmacology)">Absorption</a></li> <li><a href="/wiki/Distribution_(pharmacology)" title="Distribution (pharmacology)">Distribution</a></li> <li><a href="/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></li> <li><a href="/wiki/Excretion" title="Excretion">Excretion</a> (<a href="/wiki/Clearance_(pharmacology)" title="Clearance (pharmacology)">Clearance</a>)</li></ul> </div></td></tr></tbody></table><div> <ul><li><a href="/wiki/Compartment_(pharmacokinetics)" title="Compartment (pharmacokinetics)">Compartment</a></li> <li><a href="/wiki/Bioequivalence" title="Bioequivalence">Bioequivalence</a></li></ul></div></td></tr><tr><th scope="row" class="navbox-group" style="width:1%;text-align: center;">Related<br /> fields</th><td class="navbox-list-with-group navbox-list navbox-odd hlist" style="width:100%;padding:0"><div style="padding:0 0.25em"></div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Neuroscience_and_psychology" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Neuroscience" title="Neuroscience">Neuroscience</a> and <a href="/wiki/Psychology" title="Psychology">psychology</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <li><a href="/wiki/Neuropsychopharmacology" title="Neuropsychopharmacology">Neuropsychopharmacology</a></li> <li><a href="/wiki/Neuropharmacology" title="Neuropharmacology">Neuropharmacology</a></li> <li><a href="/wiki/Psychopharmacology" title="Psychopharmacology">Psychopharmacology</a></li> <li><a href="/wiki/Electrophysiology" title="Electrophysiology">Electrophysiology</a></li> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Medicine" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Medicine" title="Medicine">Medicine</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Clinical_pharmacology" title="Clinical pharmacology">Clinical pharmacology</a></li> <li><a href="/wiki/Pharmacy" title="Pharmacy">Pharmacy</a></li> <li><a href="/wiki/Medicinal_chemistry" title="Medicinal chemistry">Medicinal chemistry</a></li> <li><a href="/wiki/Pharmacoepidemiology" title="Pharmacoepidemiology">Pharmacoepidemiology</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Biochemistry_and_genetics" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Biochemistry" title="Biochemistry">Biochemistry</a> and <a href="/wiki/Genetics" title="Genetics">genetics</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Pharmacoinformatics" title="Pharmacoinformatics">Pharmacoinformatics</a></li> <li><a href="/wiki/Pharmacogenetics" class="mw-redirect" title="Pharmacogenetics">Pharmacogenetics</a></li> <li><a href="/wiki/Pharmacogenomics" title="Pharmacogenomics">Pharmacogenomics</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Toxicology" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Toxicology" title="Toxicology">Toxicology</a></th><td class="navbox-list-with-group navbox-list navbox-even" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Pharmacotoxicology" title="Pharmacotoxicology">Pharmacotoxicology</a></li> <li><a href="/wiki/Neurotoxicology" class="mw-redirect" title="Neurotoxicology">Neurotoxicology</a></li></ul> </div></td></tr></tbody></table><div> </div><table class="nowraplinks navbox-subgroup" style="border-spacing:0"><tbody><tr><th id="Drug_discovery" scope="row" class="navbox-group" style="width:1%;text-align: center;"><a href="/wiki/Drug_discovery" title="Drug discovery">Drug discovery</a></th><td class="navbox-list-with-group navbox-list navbox-odd" style="width:100%;padding:0"><div style="padding:0 0.25em"> <ul><li><a href="/wiki/Classical_pharmacology" title="Classical pharmacology">Classical pharmacology</a></li> <li><a href="/wiki/Reverse_pharmacology" title="Reverse pharmacology">Reverse pharmacology</a></li></ul> </div></td></tr></tbody></table><div> <ul><li><a href="/wiki/Photopharmacology" title="Photopharmacology">Photopharmacology</a></li> <li><a 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