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 the therapeutic effect to the amount that causes toxicity.[1] The related terms therapeutic window or safety window refer to a range of doses which optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or 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) 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). Today, more sophisticated toxicity endpoints are used.

in animal studies, or for humans,

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.[3]

TermMeaning
EDEffective Dose
TDToxic Dose
LDLethal Dose
TITherapeutic Index
TRTherapeutic Ratio

Therapeutic index in drug development

A high therapeutic index (TI) is preferable for a drug to have a favorable safety and efficacy 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.[2]

Range of therapeutic indices

The therapeutic index varies widely among substances, even within a related group.

For instance, the opioid 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.[4] Morphine is even less so with a therapeutic index of 70.

Less safe are cocaine (a stimulant and local anaesthetic) and ethanol (colloquially, the "alcohol" in alcoholic beverages, a widely available sedative consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively.[5]

Even less safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1.[6]

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

Cancer radiotherapy

Radiotherapy aims to minimize the size of tumors and kill cancer cells with high energy. The source of high energy arises from x-rays, gamma rays, charged particles and heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is related to the maximum radiation dose by which death of cancer cells is locally controlled and the minimum radiation dose by which cells in normal tissues have low acute and late morbidity.[7] Both of parameters have sigmoidal dose-response curves. Thus, a favorable outcome in dose-response curve is the response of tumor tissue is greater than that of normal tissue to the same dose, meaning that the treatment is effective to tumors and does not cause serious morbidity to normal tissue. Reversely, overlapping response of two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment to tumors. The mechanism of radiation therapy is categorized into direct and indirect radiation. Both of direct and indirect radiations induce DNAs to have a mutation or chromosomal rearrangement during its repair process. Direct radiation creates a free DNA radical from radiation energy deposition that damages DNA. Indirect radiation occurs from radiolysis of water, creating a free hydroxyl radical, hydronium and electron. Then, hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage base region of DNA.[8]

Cancer cells have imbalance of signals in cell cycle. G1 and G2/M arrest are found to be major checkpoints by irradiation in human cells. G1 arrest delays repair mechanism before synthesis of DNA in S phase and mitosis in M phase, suggesting key checkpoint to lead survival of cells. G2/M arrest occurs when cells need to repair after S phase before the mitotic entry. It was also known that S phase is the most resistant to radiation and M phase was 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 by radiation. For example, irradiation to myeloid leukemia cell 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.[9] In this case, cells are able to replicate without repair of their DNA, prone to incidence of cancer. Most cells are in G1 and S phase and irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been on focus for therapeutic treatment. Irradiation to a tissue creates response to both irradiated and non-irridiated cells. It was found that even cells up to 50–75 cell diameter distant from irradiated cells have phenotype of enhanced genetic instability such as micronucleation.[10] This suggests the effect of cell-to-cell communication such as paracrine and juxtacrine signaling. Normal cells do not lose DNA repair mechanism whereas cancer cells often lose during radiotherapy. However, the nature of high energy radiation can override the ability of damaged normal cell to repair, leading to cause another risk for 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 dose to normal tissues by altered fractionation. Molecular targeting to DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA double-strand breaks. Direct inhibitors target proteins (PARP family) and kinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target proteins tumor cell signaling proteins such as EGFR and insulin growth factor.[7]

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.

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.[5] 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 to 99% of the population (LD1/ED99).[11] 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.

Synergistic effect

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

The 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.[12] 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, 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 treatment that will produce the desired effect without unacceptable toxicity.[13][14] 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.

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 patients 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

References
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  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.
  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.
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  7. Thoms J, Bristow RG (October 2010). "DNA repair targeting and radiotherapy: a focus on the therapeutic ratio". Seminars in Radiation Oncology. 20 (4): 217–22. doi:10.1016/j.semradonc.2010.06.003. PMID 20832013.
  8. Yokoya A, Shikazono N, Fujii K, Urushibara A, Akamatsu K, Watanabe R (2008-10-01). "DNA damage induced by the direct effect of radiation". Radiation Physics and Chemistry. The International Symposium on Charged Particle and Photon Interaction with Matter – ASR 2007. 77 (10–12): 1280–85. doi:10.1016/j.radphyschem.2008.05.021.
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  10. Soriani RR, Satomi LC, Pinto Td (2005-07-01). "Effects of ionizing radiation in ginkgo and guarana". Radiation Physics and Chemistry. 73 (4): 239–42. doi:10.1016/j.radphyschem.2005.01.003.
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  14.  This article incorporates public domain material from the Congressional Research Service document: Jasper Womach. "Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition" (PDF).
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