Editing Therapeutic index

{{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"/>
|}

==Types==
Based on [[efficacy (pharmacology)|efficacy]] and [[drug safety|safety]] of drugs, there are two types of therapeutic index:

;Safety-based therapeutic index
<math>TI_\text{safety} = \frac{LD_{50}}{ED_{50}}</math><br/>
It is desirous for the value of LD{{sub|50}} to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TI{{sub|safety}} increases as the difference between LD{{sub|50}} and ED{{sub|50}} increases—hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vice versa.

;Efficacy-based therapeutic index
<math>TI_\text{efficacy} = \frac{ED_{50}}{TD_{50}}</math><br/>
Ideally the ED{{sub|50}} is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD{{sub|50}} is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED{{sub|50}} and TD{{sub|50}}, the greater the value of TI{{sub|efficacy}}. Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window.

;Protective index
Similar to safety-based therapeutic index, the [[protective index]] uses TD<sub>50</sub> (median ''toxic'' dose) in place of LD<sub>50</sub>.

<math>\text{Protective index} = \frac{TD_{50}}{ED_{50}} = \frac{1}{TI_\text{efficacy}}</math>

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 (<math>{TI_\text{safety}}</math>) is still useful as it can be considered an [[upper bound]] of the protective index, and the former also has the advantages of objectivity and easier comprehension.

Since the protective index (PI) is calculated as TD{{sub|50}} divided by ED{{sub|50}}, it can be mathematically expressed that:
:<math>TI_\text{efficacy} = \frac{1}\text{Protective index}</math>
which means that <math>TI_\text{efficacy}</math> is a [[multiplicative inverse|reciprocal]] of protective index.

All the above types of therapeutic index can be used in both [[pre-clinical trial]]s and [[clinical trial]]s.

==Drug development==
A low efficacy-based therapeutic index (<math>TI_\text{efficacy}</math>) and a high safety-based therapeutic index (<math>TI_\text{safety}</math>) 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.

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.

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.

A review published by Muller PY and Milton MN in ''[[Nature Reviews Drug Discovery]]'' critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.<ref name="muller-Milton2012"/>

==Range of therapeutic indices==
The therapeutic index varies widely among substances, even within a related group.

For instance, the [[opioid]] [[analgesics|painkiller]] [[remifentanil]] is very forgiving, offering a therapeutic index of 33,000:1, while [[Diazepam]], a [[benzodiazepine]] [[sedative-hypnotic]] and skeletal [[muscle relaxant]], has a less forgiving therapeutic index of 100:1.<ref>{{cite journal | vauthors = Stanley TH | title = Anesthesia for the 21st century | journal = Proceedings | volume = 13 | issue = 1 | pages = 7–10 | date = January 2000 | pmid = 16389318 | pmc = 1312206 | doi = 10.1080/08998280.2000.11927635 }}</ref> Morphine is even less so with a therapeutic index of 70.

Less safe are [[cocaine]] (a [[stimulant]] and [[local anaesthetic]]) and [[ethanol]] (a [[sedative]]): the therapeutic indices for these substances are 15:1 and 10:1, respectively.<ref name="Drug comparison" /> [[Paracetamol]], alternatively known by its trade names [[Tylenol (brand)|Tylenol]] or Panadol, also has a therapeutic index of 10.<ref>{{cite journal| vauthors=Bertolini A, Ferrari A, et al|title=Paracetamol New Vistas of an Old Drug|year=2006 |journal= CNS Drug Reviews|volume=12 |issue=3–4 |pages=250–275 |doi=10.1111/j.1527-3458.2006.00250.x |pmid=17227290 |pmc=6506194 }} Vol. 12, No. 3–4, pp. 250–275</ref>

Even less safe are drugs such as [[digoxin]], a [[cardiac glycoside]]; its therapeutic index is approximately 2:1.<ref>{{cite journal | vauthors = Becker DE | title = Drug therapy in dental practice: general principles. Part 2 – pharmacodynamic considerations | journal = Anesthesia Progress | volume = 54 | issue = 1 | pages = 19–23; quiz 24–25 | date = Spring 2007 | pmid = 17352523 | pmc = 1821133 | doi = 10.2344/0003-3006(2007)54[19:DTIDPG]2.0.CO;2 }}</ref>

Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include [[dimercaprol]], [[theophylline]], [[warfarin]] and [[lithium carbonate]].

Some antibiotics and antifungals require monitoring to balance efficacy with minimizing [[adverse effect]]s, including: [[gentamicin]], [[vancomycin]], [[amphotericin B]] (nicknamed 'amphoterrible' for this very reason), and [[polymyxin B]].

===Cancer radiotherapy===
Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from [[x-ray]]s, [[gamma ray]]s, or [[charged particle|charged]] 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.<ref name="Thoms 217–222">{{cite journal | vauthors = Thoms J, Bristow RG | title = DNA repair targeting and radiotherapy: a focus on the therapeutic ratio | journal = Seminars in Radiation Oncology | volume = 20 | issue = 4 | pages = 217–22 | date = October 2010 | pmid = 20832013 | doi = 10.1016/j.semradonc.2010.06.003 }}</ref> Both of these parameters have [[sigmoid function|sigmoidal]] [[dose–response curve]]s. 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 [[DNA mutation]] or [[chromosomal rearrangement]] during its repair process. Direct radiation creates a DNA [[free radical]] from radiation energy deposition that damages DNA. Indirect radiation occurs from [[radiolysis]] of water, creating a free [[hydroxyl radical]], [[hydronium]] 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.<ref>{{cite journal | last1 = Yokoya | first1 = A. | last2 = Shikazono | first2 = N. | last3 = Fujii | first3 = K. | last4 = Urushibara | first4 = A. | last5 = Akamatsu | first5 = K. | last6 = Watanabe | first6 = R. | name-list-style = vanc | date = 2008-10-01 | title = DNA damage induced by the direct effect of radiation | journal = Radiation Physics and Chemistry | series = The International Symposium on Charged Particle and Photon Interaction with Matter – ASR 2007 | volume = 77 | issue = 10–12 | pages = 1280–85 | doi =10.1016/j.radphyschem.2008.05.021 | bibcode = 2008RaPC...77.1280Y}}</ref>
 
Cancer cells cause an imbalance of signals in the [[cell cycle]]. 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 [[S phase]] and [[mitosis]] 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. [[p53]], 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 [[myeloid leukemia]] cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with [[Ataxia telangiectasia]] delays have hypersensitivity to radiation due to the delay of accumulation of p53.<ref>{{Cite web|url=http://www.cancer.gov/about-cancer/causes-prevention/genetics/ataxia-fact-sheet#q1|title=Ataxia Telangiectasia|website=National Cancer Institute|access-date=2016-04-11}}</ref> 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 [[phenotype]] of enhanced genetic instability such as micronucleation.<ref>{{cite journal | last1 = Soriani | first1 = Renata Rabelo | last2 = Satomi | first2 = Lucilia Cristina | last3 = Pinto | first3 = Terezinha de Jesus A. | name-list-style = vanc | date = 2005-07-01 | title = Effects of ionizing radiation in ginkgo and guarana | journal = Radiation Physics and Chemistry | volume = 73 | issue = 4 | pages = 239–42 | doi = 10.1016/j.radphyschem.2005.01.003}}</ref> This suggests an effect on cell-to-cell communication such as [[paracrine]] and [[juxtacrine signaling]]. Normal cells do not lose their [[DNA repair]] 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 [[carcinogenesis]]. 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 [[double-strand break]]s. Direct inhibitors target proteins ([[Poly ADP ribose polymerase|PARP family]]) and [[kinases]] (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as [[Epidermal growth factor receptor|EGFR]] and [[insulin growth factor]].<ref name="Thoms 217–222"/>

The effective therapeutic index can be affected by [[Targeted drug delivery|targeting]], in which the therapeutic agent is concentrated in its desirable area of effect. For example, in [[Radiation treatment|radiation therapy]] 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 [[peptide receptor radionuclide therapy]] for [[neuroendocrine tumors]] and in [[chemoembolization]] 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.

==Safety ratio==
Sometimes the term '''safety ratio''' is used, particularly when referring to [[psychoactive drugs]] used for non-therapeutic purposes, e.g. recreational use.<ref name="Drug comparison">{{cite journal | vauthors = Gable RS | title = Comparison of acute lethal toxicity of commonly abused psychoactive substances | journal = Addiction | volume = 99 | issue = 6 | pages = 686–96 | date = June 2004 | pmid = 15139867 | doi = 10.1111/j.1360-0443.2004.00744.x | url = http://rgable.files.wordpress.com/2012/02/toxicity-addiction-offprint2.pdf }}</ref> In such cases, the ''effective'' dose is the amount and frequency that produces the ''desired'' effect, which can vary, and can be greater or less than the therapeutically effective dose.

The ''Certain Safety Factor'', also referred to as the ''Margin of Safety (MOS)'', is the ratio of the [[lethal dose]] to 1% of population to the [[Effective dose (pharmacology)|effective dose]] to 99% of the population (LD{{sub|1}}/ED{{sub|99}}).<ref>{{cite web|url=http://www2.courses.vcu.edu/ptxed/m2/faqs_damaj.htm|title=FAQs: Dr. Damaj|access-date=4 October 2015}}</ref> This is a better safety index than the [[Median lethal dose|LD<sub>50</sub>]] 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.

:<math>\text{Certain safety factor} = \mathrm{\frac{LD_1}{ED_{99}}}</math>

==Synergistic effect==
A therapeutic index does not consider drug interactions or [[synergy|synergistic]] effects. For example, the risk associated with [[benzodiazepine]]s increases significantly when taken with alcohol,<ref name="nhsinform.scot" /><ref name="nida.nih.gov"/><ref name="samhsa.gov" /> depressants,<ref name="nhsinform.scot">{{cite web|url=https://www.nhsinform.scot/healthy-living/drugs-and-drug-use/common-drugs/benzodiazepines-benzos-diazepam-valium/|title=Benzodiazepines (benzos, diazepam, valium)|publisher=[[NHS Information Authority]]|archive-url=https://archive.today/20250218195514/https://www.nhsinform.scot/healthy-living/drugs-and-drug-use/common-drugs/benzodiazepines-benzos-diazepam-valium/|archive-date=February 18, 2025|url-status=live |quote=Mixing benzodiazepines with other drugs increases the risk of harm. Mixing benzodiazepines with alcohol and other depressants like heroin increases their effects and can increase toxicity. They slow down the central nervous system, increasing the risk of overdose.}}</ref> opiates,<ref name="nida.nih.gov">{{cite web|url=https://nida.nih.gov/research-topics/opioids/benzodiazepines-opioids|title=Benzodiazepines and Opioids|date=7 November 2022 |publisher=[[National Institute on Drug Abuse]]|archive-url=https://archive.today/20250218200219/https://web.archive.org/web/20220607142621/https://nida.nih.gov/research-topics/opioids/benzodiazepines-opioids|archive-date=February 18, 2025|access-date=February 18, 2025|url-status=live|quote=Taking opioids in combination with other central nervous system depressants—like benzodiazepines, alcohol, or xylazine—increases the risk of life-threatening overdose.}}</ref><ref>{{cite journal |doi=10.1016/j.drugpo.2022.103933 |quote=For example, a recent study conducted in Canada showed that concurrent use of opioids and benzodiazepines carried a 13% higher risk of hospitalization or emergency department visits, and almost doubled the risk of death |title=The increase in benzodiazepine-laced drugs and related risks in Canada: The urgent need for effective and sustainable solutions |date=2023 |last1=Russell |first1=Cayley |last2=Law |first2=Justine |last3=Bonn |first3=Matthew |last4=Rehm |first4=Jürgen |last5=Ali |first5=Farihah |journal=International Journal of Drug Policy |volume=111 |pmid=36529033 }} (Citing {{cite journal |doi=10.1136/bmjopen-2020-038692 |title=Concurrent use of opioids and benzodiazepines/Z-drugs in Alberta, Canada and the risk of hospitalisation and death: A case cross-over study |date=2020 |last1=Sharma |first1=Vishal |last2=Simpson |first2=Scot H. |last3=Samanani |first3=Salim |last4=Jess |first4=Ed |last5=Eurich |first5=Dean T. |journal=BMJ Open |volume=10 |issue=11 |pages=e038692 |pmid=33444187 }})</ref><ref>{{cite journal |doi=10.1016/j.drugalcdep.2012.07.004 |quote=Our search found approximately 200 articles appropriate for inclusion...The co-abuse of BZDs and opioids is substantial and has negative consequences for general health, overdose lethality, and treatment outcome. |title=Polydrug abuse: A review of opioid and benzodiazepine combination use |date=2012 |last1=Jones |first1=Jermaine D. |last2=Mogali |first2=Shanthi |last3=Comer |first3=Sandra D. |journal=Drug and Alcohol Dependence |volume=125 |issue=1–2 |pages=8–18 |pmid=22857878 }}</ref><ref name="samhsa.gov">{{cite web|url=https://www.samhsa.gov/data/sites/default/files/DAWN-SR192-BenzoCombos-2014/DAWN-SR192-BenzoCombos-2014.htm|title=Benzodiazepines in Combination with Opioid Pain Relievers or Alcohol: Greater Risk of More Serious ED Visit Outcomes|publisher=[[Substance Abuse and Mental Health Services Administration]]|date=December 18, 2014|archive-url=https://archive.today/20200923001950/https://www.samhsa.gov/data/sites/default/files/DAWN-SR192-BenzoCombos-2014/DAWN-SR192-BenzoCombos-2014.htm|archive-date=September 23, 2020|url-status=live|quote=Combining benzodiazepines with opioid pain relievers or alcohol significantly increases the risk of a more serious ED [Emergency Department] visit outcome.}}</ref><ref>{{cite journal|url=https://publications.ersnet.org/content/erjor/6/3/00093-2020|title=Concomitant benzodiazepine and opioids decrease sleep apnoea risk in chronic pain patients|journal=ERJ Open Research|volume=6|issue=3|year=2020|doi=10.1183/23120541.00093-2020|archive-url=https://archive.today/20250218202133/https://publications.ersnet.org/content/erjor/6/3/00093-2020|archive-date=February 18, 2025|url-status=live|pmc=7445118 |last1=Mir |first1=Soodaba |last2=Wong |first2=Jean |last3=Ryan |first3=Clodagh M. |last4=Bellingham |first4=Geoff |last5=Singh |first5=Mandeep |last6=Waseem |first6=Rida |last7=Eckert |first7=Danny J. |last8=Chung |first8=Frances |pages=00093–2020 |pmid=32864381 |quote=In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild [[respiratory depression]] but paradoxically reduced [[sleep apnoea]] risk and severity by increasing the respiratory arousal threshold.}}</ref> or stimulants<ref>Quote: "Benzos enhance the opioid high but actually dampen the rewarding effects of stimulants (Lile JA et al, Drug Alcohol Depend 2011;119(3):187–193). That is particularly true with oxazepam, which is unique among the benzos for its ability to raise neurosteroids that block the rewarding properties of drugs of abuse (Spence AL et al, Drug Alcohol Depend 2016;166:209–217). Oxazepam also has a lower abuse liability than most benzodiazepines when used on its own. On the other hand, amphetamines can lead to benzodiazepine abuse, as patients often turn to benzodiazepines to ease anxiety and other undesirable effects of amphetamines (Darke S et al, Addiction 1994;89(12):1683–1690). That pattern also shows up in practice when clinicians prescribe one drug to manage the side effects of the other." {{cite web|author=Chris Eiken, MD|url=https://www.thecarlatreport.com/articles/4105-the-benzodiazepine-stimulant-combo-what-could-go-wrong|title=The Benzodiazepine-Stimulant Combo: What Could Go Wrong?|date=September 25, 2022|archive-url=https://archive.today/20250218203018/https://www.thecarlatreport.com/articles/4105-the-benzodiazepine-stimulant-combo-what-could-go-wrong|archive-date=February 18, 2025|url-status=live}}} (via: ''[[Daniel Carlat|The Carlat Psychiatry Report]]'')</ref> when compared with being taken alone. 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.

==Therapeutic window==
The ''therapeutic window'' (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects.<ref>{{cite book | last1 = Rang | first1 = H.P. | name-list-style = vanc | title = Rang & Dale's Pharmacology | date = 2015 | publisher = Churchill Livingstone | isbn = 978-0-7020-5362-7 | section = Pharmacokinetics | pages = 125 | edition = 8th | display-authors = etal }}</ref> 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 [[theophylline]], [[digoxin]], [[lithium (medication)|lithium]], and [[warfarin]].

==Optimal biological dose==
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.

==Maximum tolerated dose==
The '''maximum tolerated dose''' (MTD) refers to the highest dose of a radiological or [[pharmacological agent|pharmacological]] treatment that will produce the desired effect without unacceptable [[toxicity]].<ref>{{cite web |publisher= National Cancer Institute |access-date=26 July 2010|url=http://www.cancer.gov/dictionary/?CdrID=546597 |title=maximum tolerated dose |work=Dictionary of Cancer Terms}}</ref><ref>{{CRS|article = Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition|url = http://ncseonline.org/nle/crsreports/05jun/97-905.pdf|author= Jasper Womach}}</ref> The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable [[adverse health effect]]s in a population, when the level of exposure is not sufficient to cause premature [[mortality rate|mortality]] due to short-term [[toxic effect]]s. The maximum dose is used, rather than a lower dose, to reduce the number of [[human subjects research|test subjects]] (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 [[chemical residue]] tolerances in foods. Maximum tolerated dose studies are also done in [[clinical trials]].

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.

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, [[pruritus]] with [[opiates]], and blurred vision with [[anticholinergics]].

==See also==
*[[Drug titration]] – process of finding the correct dose of a drug
*[[Effective dose (pharmacology)|Effective dose]]
* [[EC50]]
* [[IC50]]
* [[LD50]]
* [[Hormesis]]

==References==
{{Reflist|33em}}

{{Pharmacology}}

[[Category:Pharmacokinetics]]
[[Category:Life sciences industry]]