Therapeutic index

The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect.^[1] 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 indications of an approved drug, TI refers to the ratio of the 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, TD₅₀) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED₅₀). In contrast, in a drug development setting TI is calculated based on plasma exposure levels.^[2]

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) divided by the minimum effective dose for 50% of the population (ED₅₀). 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 due to its narrow therapeutic range.^[3]

Term	Full form	Definition
ED	Effective Dose	the dose or concentration of a drug that produces a biological response.^[4]^[5]
TD	Toxic Dose	the dose at which toxicity occurs in 50% of cases.
LD	Lethal Dose	the dose at which toxicity occurs in 50% of cases.^[6]^: 73
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^[7]

^ Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). "Chapter 2: Pharmacodynamics". Pharmacology Examination & Board Review (10th ed.). New York: McGraw-Hill Medical. p. 17. ISBN 978-0-07-178924-0. The therapeutic index is the ratio of the TD₅₀ (or LD₅₀) to the ED₅₀, determined from quantal dose–response curves.
^ Muller PY, Milton MN (October 2012). "The determination and interpretation of the therapeutic index in drug development". Nature Reviews. Drug Discovery. 11 (10): 751–61. doi:10.1038/nrd3801. PMID 22935759. S2CID 29777090.
^ Ratanajamit C, Soorapan S, Doang-ngern T, Waenwaisart W, Suwanchavalit L, Suwansiri S, Jantasaro S, Yanate I (November 2006). "Appropriateness of therapeutic drug monitoring for lithium". Journal of the Medical Association of Thailand = Chotmaihet Thangphaet. 89 (11): 1954–60. PMID 17205880.
^ Filloon, T. G. (May 1995). "Estimating the minimum therapeutically effective dose of a compound via regression modelling and percentile estimation". Statistics in Medicine. 14 (9–10): 925–932, discussion 933. doi:10.1002/sim.4780140911. ISSN 0277-6715. PMID 7569511.
^ Street, Farnam (2014-02-13). "The Minimum Effective Dose: Why Less is More". Farnam Street. Retrieved 2023-05-23.
^ Goodman, Louis S. (2011). Brunton, Laurence L.; Chabner, Bruce; Knollmann, Björn C. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12 ed.). New York: McGraw-Hill. ISBN 9780071624428.
^ Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). "Chapter 2: Pharmacodynamics". Pharmacology Examination & Board Review (10th ed.). New York: McGraw-Hill Medical. p. 17. ISBN 978-0-07-178924-0. The therapeutic index is the ratio of the TD₅₀ (or LD₅₀) to the ED₅₀, determined from quantal dose–response curves.

[1] Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). "Chapter 2: Pharmacodynamics". Pharmacology Examination & Board Review (10th ed.). New York: McGraw-Hill Medical. p. 17. ISBN 978-0-07-178924-0. The therapeutic index is the ratio of the TD₅₀ (or LD₅₀) to the ED₅₀, determined from quantal dose–response curves.

[muller-Milton2012-2] Muller PY, Milton MN (October 2012). "The determination and interpretation of the therapeutic index in drug development". Nature Reviews. Drug Discovery. 11 (10): 751–61. doi:10.1038/nrd3801. PMID 22935759. S2CID 29777090.

[3] Ratanajamit C, Soorapan S, Doang-ngern T, Waenwaisart W, Suwanchavalit L, Suwansiri S, Jantasaro S, Yanate I (November 2006). "Appropriateness of therapeutic drug monitoring for lithium". Journal of the Medical Association of Thailand = Chotmaihet Thangphaet. 89 (11): 1954–60. PMID 17205880.

[4] Filloon, T. G. (May 1995). "Estimating the minimum therapeutically effective dose of a compound via regression modelling and percentile estimation". Statistics in Medicine. 14 (9–10): 925–932, discussion 933. doi:10.1002/sim.4780140911. ISSN 0277-6715. PMID 7569511.

[5] Street, Farnam (2014-02-13). "The Minimum Effective Dose: Why Less is More". Farnam Street. Retrieved 2023-05-23.

[Goodman_&_Gilman2011-6] Goodman, Louis S. (2011). Brunton, Laurence L.; Chabner, Bruce; Knollmann, Björn C. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12 ed.). New York: McGraw-Hill. ISBN 9780071624428.

[7] Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). "Chapter 2: Pharmacodynamics". Pharmacology Examination & Board Review (10th ed.). New York: McGraw-Hill Medical. p. 17. ISBN 978-0-07-178924-0. The therapeutic index is the ratio of the TD₅₀ (or LD₅₀) to the ED₅₀, determined from quantal dose–response curves.

[1]

[2]

[3]

[4]

[5]

[6]

[7]