Thetherapeutic index (TI; also referred to astherapeutic 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 thetherapeutic effect.[1] The related termstherapeutic window orsafety 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 clinicalindications of an approved drug, TI refers to the ratio of thedose 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 adrug development setting TI is calculated based on plasmaexposure 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 minimumeffective 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 throughtherapeutic drug monitoring (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders withlithium due to its narrow therapeutic range.[3]
| Term | Full form | Definition |
|---|---|---|
| ED | Effective Dose | thedose orconcentration of adrug that produces a biological response.[4][5] |
| TD | Toxic Dose | the dose at whichtoxicity occurs in 50% of cases. |
| LD | Lethal Dose | the dose at whichdeath occurs in 50% of cases.[6]: 73 [7][8] |
| 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[1] |
Based onefficacy andsafety of drugs, there are two types of therapeutic index:
It is desirous for the value of LD50 to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TIsafety increases as the difference between LD50 and ED50 increases—hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vice versa.
Ideally the ED50 is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD50 is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED50 and TD50, the greater the value of TIefficacy. Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window.
Similar to safety-based therapeutic index, theprotective index uses TD50 (mediantoxic dose) in place of LD50.
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 () is still useful as it can be considered anupper 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 TD50 divided by ED50, it can be mathematically expressed that:
which means that is areciprocal of protective index.
All the above types of therapeutic index can be used in bothpre-clinical trials andclinical trials.
A low efficacy-based therapeutic index () and a high safety-based therapeutic index () 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 inNature Reviews Drug Discovery critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.[2]
The therapeutic index varies widely among substances, even within a related group.
For instance, theopioidpainkillerremifentanil is very forgiving, offering a therapeutic index of 33,000:1, whileDiazepam, abenzodiazepinesedative-hypnotic and skeletalmuscle relaxant, has a less forgiving therapeutic index of 100:1.[9] Morphine is even less so with a therapeutic index of 70.
Less safe arecocaine (astimulant andlocal anaesthetic) andethanol (asedative): the therapeutic indices for these substances are 15:1 and 10:1, respectively.[10]Paracetamol, alternatively known by its trade namesTylenol or Panadol, also has a therapeutic index of 10.[11]
Even less safe are drugs such asdigoxin, acardiac glycoside; its therapeutic index is approximately 2:1.[12]
Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, includedimercaprol,theophylline,warfarin andlithium carbonate.
Some antibiotics and antifungals require monitoring to balance efficacy with minimizingadverse effects, including:gentamicin,vancomycin,amphotericin B (nicknamed 'amphoterrible' for this very reason), andpolymyxin B.
Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises fromx-rays,gamma rays, orcharged 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.[13] Both of these parameters havesigmoidaldose–response curves. 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 induceDNA mutation orchromosomal rearrangement during its repair process. Direct radiation creates a DNAfree radical from radiation energy deposition that damages DNA. Indirect radiation occurs fromradiolysis of water, creating a freehydroxyl 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.[14]
Cancer cells cause an imbalance of signals in thecell 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 inS phase andmitosis 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 ofmyeloid leukemia cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients withAtaxia telangiectasia delays have hypersensitivity to radiation due to the delay of accumulation of p53.[15] 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 aphenotype of enhanced genetic instability such as micronucleation.[16] This suggests an effect on cell-to-cell communication such asparacrine andjuxtacrine signaling. Normal cells do not lose theirDNA 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 ofcarcinogenesis. 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 DNAdouble-strand breaks. Direct inhibitors target proteins (PARP family) andkinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such asEGFR andinsulin growth factor.[13]
The effective therapeutic index can be affected bytargeting, in which the therapeutic agent is concentrated in its desirable area of effect. For example, inradiation 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 inpeptide receptor radionuclide therapy forneuroendocrine tumors and inchemoembolization 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.
Sometimes the termsafety ratio is used, particularly when referring topsychoactive drugs used for non-therapeutic purposes, e.g. recreational use.[10] In such cases, theeffective dose is the amount and frequency that produces thedesired effect, which can vary, and can be greater or less than the therapeutically effective dose.
TheCertain Safety Factor, also referred to as theMargin of Safety (MOS), is the ratio of thelethal dose to 1% of population to theeffective dose to 99% of the population (LD1/ED99).[17] This is a better safety index than theLD50 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.
A therapeutic index does not consider drug interactions orsynergistic effects. For example, the risk associated withbenzodiazepines increases significantly when taken with alcohol,[18][19][20] depressants,[18] opiates,[19][21][22][20][23] or stimulants[24] 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.
Thetherapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects.[25] 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 includetheophylline,digoxin,lithium, andwarfarin.
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.
Themaximum tolerated dose (MTD) refers to the highest dose of a radiological orpharmacological treatment that will produce the desired effect without unacceptabletoxicity.[26][27] The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptableadverse health effects in a population, when the level of exposure is not sufficient to cause prematuremortality due to short-termtoxic effects. The maximum dose is used, rather than a lower dose, to reduce the number oftest 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 establishingchemical residue tolerances in foods. Maximum tolerated dose studies are also done inclinical 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 withopiates, and blurred vision withanticholinergics.
The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose–response curves.
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.
Taking opioids in combination with other central nervous system depressants—like benzodiazepines, alcohol, or xylazine—increases the risk of life-threatening overdose.
Combining benzodiazepines with opioid pain relievers or alcohol significantly increases the risk of a more serious ED [Emergency Department] visit outcome.
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(CitingSharma, Vishal; Simpson, Scot H.; Samanani, Salim; Jess, Ed; Eurich, Dean T. (2020)."Concurrent use of opioids and benzodiazepines/Z-drugs in Alberta, Canada and the risk of hospitalisation and death: A case cross-over study".BMJ Open.10 (11) e038692.doi:10.1136/bmjopen-2020-038692.PMC 7682464.PMID 33444187.)
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.
In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mildrespiratory depression but paradoxically reducedsleep apnoea risk and severity by increasing the respiratory arousal threshold.
This article incorporatespublic domain material fromJasper Womach.Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition(PDF).Congressional Research Service.