Therapeutic Index: What It Is and Why It’s Important

The therapeutic index is a measurement of drug safety and plays a key role in drug development. It is the relationship between therapeutic (effective) and toxic drug concentrations. Please continue reading to learn more.

What is therapeutic index, therapeutic ratio, and therapeutic window in drug therapy?

The therapeutic index (TI) is also called the therapeutic ratio or therapeutic window. It is a quantitative measure of the relative safety of a drug. The therapeutic index compares effective and toxic doses, i.e., drug doses that have therapeutic effects and drug doses that cause severe adverse drug reactions or drug toxicity.

The therapeutic window refers to a range of doses that are optimized for therapeutic effects without causing toxicity in clinical settings. For example, if the therapeutic window of a drug is 100 milligrams (mg) to 500 mg per day, it means these are the doses at which the drug will be effective without causing serious adverse effects. A dose or blood concentration lower than this range may result in serious therapeutic failures (lack of effectiveness or treatment failure). A dose higher than this range could be a toxic dose and may cause persistent or significant disability.

Therefore, when a drug has a narrow therapeutic index (or window), a slight difference in dose or blood concentration (the amount of drug in the body) can result in treatment failure, serious adverse effects, or both.

The adverse effects and toxicity associated with a particular drug can be significantly increased by certain health complications and medications. However, the therapeutic index does not take into account drug interactions or variability in renal or hepatic function, which can alter the therapeutic dose in some medications.

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Do you want a high or low therapeutic index?

You want a high therapeutic index. The higher the therapeutic index, the safer the drug. The lower the therapeutic index, the more risk there is for adverse reactions, toxic effects, and treatment failure.

Drugs with a low or narrow therapeutic range are called narrow therapeutic index drugs or NTI drugs. Such drugs have small differences in dose or blood concentration that can result in negative health outcomes with serious adverse effects, ineffective treatment, or both. NTI drugs must be dosed carefully in clinical practice, requiring close monitoring and patient education. Patients may require regular monitoring with blood tests to measure the plasma levels (drug levels) of the drug and make sure it remains in the narrow therapeutic range, where the therapy is the most safe and effective.

How do you calculate the therapeutic index?

TD₅₀ (toxic dose in 50% of subjects)is the dose required to produce a toxic effect in 50% of the population. ED₅₀ (effective dose in 50% of subjects) is the dose required to produce a therapeutic effect (desired effect) in 50% of the population.

The therapeutic index is calculated as a ratio of TD₅₀ divided by ED₅₀.

What is a therapeutic index of 20?

A therapeutic index of 20 is when the toxic dose of a drug is 20 times higher than the therapeutic dose. For example, if the typical therapeutic dose of a drug is a single dose of 500 mg per day and the toxic dose is 10,000 mg, then the therapeutic ratio or therapeutic index is 10,000 mg/500 mg = 20.

A drug with a higher therapeutic index does not typically require intensive therapeutic drug monitoring. In the example above, the usual dose of the drug is 500 mg daily, and the average (median) lethal dose is 10,000 mg. Because the toxic dose is 20 times higher than the therapeutic dose, it may not require monitoring as strictly as those with a narrow therapeutic index. Your doctor will determine the monitoring plan to ensure the safety and efficacy of the treatment.

Even though a medication has a high therapeutic index, monitoring is still necessary, especially at the beginning of therapy and dosage changes. Other factors influencing monitoring/follow-up include age, health status, and other current medications.

On the other hand, if the typical effective dose of a drug is 500 mg and the toxic dose is 1,500 mg, then this narrow window may require the plasma concentration (drug levels in the bloodstream) of the given drug to be monitored closely.

What are some examples of drugs with a low therapeutic index?

Many drugs have a narrow therapeutic index. Some examples include:

Warfarin (oral anticoagulant or blood thinner to prevent and treat blood clots)
Digoxin (prescribed for congestive heart failure and heart rhythm abnormalities)
Phenytoin (antiepileptic or seizure drug)
Lithium (used to treat bipolar disorder)
Gentamicin (antibiotic)
Amphotericin B (antifungal)
Zidovudine (HIV medication)
5-fluorouracil (used for skin cancer and other cancer treatment)

Can you switch from brand name to generic drugs if the therapeutic index is narrow?

Generic drugs can be substituted for name-brand drugs provided they meet the recommended bioequivalence (BE). For narrow therapeutic index drugs, the bioequivalence range of generic drugs needs to be appropriate to ensure the drug is neither ineffective nor causes serious unwanted effects.

Switching from a brand name to its generic counterpart of a narrow therapeutic drug is allowed under the close supervision of a healthcare provider. Generic drugs allow much lower costs, so if you are interested in switching from a brand name medication to its generic version, talk to your doctor about it. Your healthcare provider may adjust the dosage and implement more stringent monitoring to ensure the treatment is still safe and effective.

Does body weight play a role in narrow therapeutic index drugs?

The patient’s recent body weight is required to accurately calculate effective doses and keep narrow therapeutic index (NTI) drugs within a safe range. This ensures efficacy and clinical response while reducing the risk of toxicity.