Editing Therapeutic index (section)

{{Short description|Quantitative measurement of the relative safety of a drug}}
{{For|more details about types of therapeutic index|Therapeutic index#Types{{!}}§ Types}}

The '''therapeutic index''' ('''TI'''; also referred to as '''therapeutic ratio''') 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 [[therapeutic effect]].<ref name="McGraw-Hill Medical">{{cite book | first1 = Anthony | last1 = Trevor | first2 = Bertram | last2 = Katzung | first3 = Susan | last3 = Masters | first4 = Marieke | last4 = Knuidering-Hall | name-list-style = vanc | title = Pharmacology Examination & Board Review | date = 2013 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-178924-0 | page = 17 | edition = 10th | chapter = Chapter 2: Pharmacodynamics |quote=The therapeutic index is the ratio of the TD<sub>50</sub> (or LD<sub>50</sub>) to the ED<sub>50</sub>, determined from quantal dose–response curves.}}</ref> The related terms '''therapeutic window''' or '''safety window''' refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

Classically, for clinical [[indication (medicine)|indication]]s of an approved drug, TI refers to the ratio of the [[dose (biochemistry)|dose]] 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, [[Median toxic dose|TD{{sub|50}}]]) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED{{sub|50}}). In contrast, in a [[drug development]] setting TI is calculated based on plasma [[wikt:exposure|exposure]] levels.<ref name="muller-Milton2012">{{cite journal | vauthors = Muller PY, Milton MN | title = The determination and interpretation of the therapeutic index in drug development | journal = Nature Reviews. Drug Discovery | volume = 11 | issue = 10 | pages = 751–61 | date = October 2012 | pmid = 22935759 | doi = 10.1038/nrd3801 | s2cid = 29777090 }}</ref>

In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population ([[LD50|LD<sub>50</sub>]]) divided by the minimum [[Effective dose (pharmacology)|effective dose]] for 50% of the population (ED<sub>50</sub>). In modern settings, more sophisticated toxicity endpoints are used.

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.

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 [[therapeutic drug monitoring]] (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with [[lithium (medication)|lithium]] due to its narrow therapeutic range.<ref>{{cite journal | vauthors = Ratanajamit C, Soorapan S, Doang-ngern T, Waenwaisart W, Suwanchavalit L, Suwansiri S, Jantasaro S, Yanate I | title = Appropriateness of therapeutic drug monitoring for lithium | journal = Journal of the Medical Association of Thailand = Chotmaihet Thangphaet | volume = 89 | issue = 11 | pages = 1954–60 | date = November 2006 | pmid = 17205880 }}</ref>

{| class="wikitable"
|-
! Term !! Full form !! Definition
|-
| ED
| Effective Dose
| the [[Dose (biochemistry)|dose]] or [[concentration]] of a [[medication|drug]] that produces a biological response.<ref>{{Cite journal |last=Filloon |first=T. G. |date=May 1995 |title=Estimating the minimum therapeutically effective dose of a compound via regression modelling and percentile estimation |url=https://pubmed.ncbi.nlm.nih.gov/7569511/ |journal=Statistics in Medicine |volume=14 |issue=9–10 |pages=925–932; discussion 933 |doi=10.1002/sim.4780140911 |issn=0277-6715 |pmid=7569511}}</ref><ref>{{Cite web |last=Street |first=Farnam |date=2014-02-13 |title=The Minimum Effective Dose: Why Less is More |url=https://fs.blog/the-minimum-effective-dose-why-less-is-more/ |access-date=2023-05-23 |website=Farnam Street |language=en-US}}</ref>
|-
| TD
| Toxic Dose
| the dose at which [[toxicity]] occurs in 50% of cases.
|-
| LD
| Lethal Dose
| the dose at which [[death]] occurs in 50% of cases.<ref name="Goodman & Gilman2011">{{cite book|title=Goodman and Gilman's The Pharmacological Basis of Therapeutics |edition=12 |url=https://books.google.com/books?id=bVUfAQAAQBAJ&q=%22lethal%20dose%22|year=2011 |last=Goodman |first=Louis S. |editor1-last=Brunton |editor1-first=Laurence L. |editor2-last=Chabner |editor2-first=Bruce |editor3-last=Knollmann |editor3-first=Björn C.|isbn=9780071624428 |location=New York |publisher=McGraw-Hill}}</ref>{{rp|73}}<ref>{{Cite journal |publisher=The International Union of Pure and Applied Chemistry (IUPAC)|title=IUPAC - median lethal dose (M03810) |url=https://goldbook.iupac.org/terms/view/M03810 |access-date=2024-07-25 |website=goldbook.iupac.org|doi=10.1351/goldbook.M03810 |doi-access=free }}</ref><ref>{{Cite web |publisher=Canadian Centre for Occupational Health and Safety |date=2024-05-10 |title=CCOHS: What is a LD₅₀ and LC₅₀? |url=https://www.ccohs.ca/oshanswers/chemicals/ld50.html |access-date=2024-07-25 |website=www.ccohs.ca}}</ref>
|-
| TI
| Therapeutic Index
| 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<ref name="McGraw-Hill Medical"/>
|}