Therapeutic index

The therapeutic index (TI) (also referred to as therapeutic window or safety window or sometimes as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.

Classically, in an established clinical indication setting of an approved drug, TI refers to the ratio of the dose of drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) divided by 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.

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). Today, more sophisticated toxicity endpoints are used.

$\mbox{Therapeutic Index} = \frac{\mathrm{LD}_{50}}{\mathrm{ED}_{50}}$ in animal studies, or for humans, $\mbox{Therapeutic Index} = \frac{\mathrm{TD}_{50}}{\mathrm{ED}_{50}}$

For many drugs, there are severe toxicities that occur at sublethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect.

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 the actual blood levels achieved 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.

Term	Meaning
'ED'	Effective Dose
'TD'	Toxic Dose
'LD'	Lethal Dose
'TI'	Therapeutic Index
'TR'	Therapeutic Ratio

Therapeutic Index in Drug Development

A high Therapeutic Index (TI) is preferable for a drug to have a favorable safety profile. At early discovery / development stage, the clinical TI of a drug candidate is not known. 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 the successful development of a drug. Recognizing drug candidates with potentially suboptimal TI at earliest possible stage helps to initiate mitigation or potentially re-deploy resources.

In a drug development setting, TI is the quantitative relationship between efficacy (pharmacology) and safety (toxicology), without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI to something that is more than just a number, 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 with the aim to create a well balanced indication-specific safety vs efficacy 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 rather than dose for calculating 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 and Milton in Nature Reviews Drug Discovery critically discusses the various aspects of TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.

Variation of Therapeutic Index

The therapeutic index varies widely among substances: most forgiving among the opioid analgesics is remifentanyl, which offers a therapeutic index of 33,000:1 while diazepam, a benzodiazepine sedative-hypnotic and skeletal muscle relaxant has a less-forgiving index of 100:1 and morphine, a sedative, antidepressant, and analgesic of herbal origin (genus Papaver) has an index of 70:1 (which, however, is still considered very safe).

Less safe are cocaine, a stimulant and local anaesthetic, and ethanol (colloquially, the "alcohol" in alcoholic beverages), a widely available sedative consumed world-wide – the therapeutic indices for these substances are 15:1 and 10:1, respectively. Even less-safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1. Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include: paracetamol (acetaminophen), dimercaprol, theophylline, warfarin and lithium carbonate. Some antibiotics require monitoring to balance efficacy with minimizing adverse effects, including: gentamicin, vancomycin, amphotericin B (nicknamed 'amphoterrible' for this very reason), and polymyxin B.

The effective therapeutic index can be affected by targeting, in which the therapeutic agent is concentrated in its area of effect. For example, in 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 is done 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.

The Safety Ratio

Sometimes the term safety ratio is used instead, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use. 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 is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population (LD1/ED99). This is a better safety index than the LD₅₀ 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.

$\mbox{Certain safety factor} = \frac{\mathrm{LD}_{1}}{\mathrm{ED}_{99}}$

Synergistic effects

A therapeutic index does not consider drug interactions or synergistic effects. For example, the risk associated with benzodiazepines increases significantly when taken with alcohol, opiates, or stimulants 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.

Protective Index

Protective index is a similar concept, except that it uses TD₅₀ (median toxic dose) in place of LD₅₀. For many substances, toxic effects can occur at levels far below those needed to cause death, and thus the protective index (if toxicity is properly specified) is often more informative about a substance's relative safety. Nevertheless, the therapeutic index is still useful as it can be considered an upper bound for the protective index, and the former also has the advantages of objectivity and easier comprehension.

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. Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm.

Optimal biological dose

Optimal biological dose (OBD) is a vague concept that refers to the quantity of a drug that will produce the desired effect with acceptable toxicity.

Maximum tolerated dose

Maximum tolerated dose (MTD) refers to the highest dose of a radiological or pharmacological treatment that will produce the desired effect without unacceptable toxicity. The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable adverse health effects in a population, when the level of exposure is not sufficient to cause premature mortality due to short-term toxic effects. The maximum dose is used, rather than a lower dose, to reduce the number of 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.

See also

• Certain safety factor
• Effective dose
• EC50
• IC50
• LD₅₀