What’s the therapeutic window of your drug?

Did we anytime think how a drug shows the effect? Why should you take not more than 25 mg of Atenolol or not more than 4000 mg of paracetamol (1000 mg per dose) or 10 mg of Cetirizine (once) per day? Why can’t we not increase or decrease the dose? Why few drugs are taken as once daily and others could be broken down to two or more times a day? These questions will be answered in this article.

When a molecule is discovered, we do not know how much of the drug gives optimal effect against the disease, how much amount of the drug precipitates to show adverse effects. For this, we carry out studies to determine the optimal amount needed to show the desired effect. This optimal range of the drug or medication is termed as therapeutic window.

Therapeutic window or pharmaceutical window is the drug concentration range in which the drug shows the desired effect. It is the range of drug dosages which can treat disease effectively while staying within the safety range. In other words, it is the dosages of a medication between the amount that gives an effect (effective dose) and the amount that gives more adverse effects than desired effects. For instance, medication with a small pharmaceutical window such as Carbamazepine must be administered with care and control, e.g. by frequently measuring blood concentration of the drug, since it easily gives adverse effects such as agranulocytosis.

But how do we determine this window? For this, the study goes back to the phase I of clinical trials. In this phase, from the data and results obtained from the preclinical or non-clinical studies, we determine the maximum concentration of the drug that can be administered to a healthy volunteer without the precipitation of adverse event. The dose is slowly increased in the volunteers and is checked for the effects. From this we get the maximum safe concentration (MSC). Next moving to phase II clinical trials which are conducted in patients with the disease for which the drug is being tested for here, we determine the minimum dose of the drug enough to show effect against the disease. This concentration of the drug that starts to fight against the disease is called as minimum effective concentration (MIC).

Let us take an example of a drug X. An immediate release dosage form of this medicament was administered to a subject orally. The amount of the active ingredient initially in the dosage form was 3 mg. The drug seemed to show no effect. Then the amount of the medicament was increased to 5 mg which was found to be good. The amount was then increased and it was found that the drug was safe till 10 mg. Therefore, the minimum amount of drug that can show effect is taken as 5 mg and the maximum safe amount was taken as 10 mg as per the experiment.

Therapeutic ratio or therapeutic index:

The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death (in animal studies) or toxicity (in human studies). Quantitatively, it is the ratio given by the lethal or toxic dose divided by the therapeutic dose. In animal studies, the therapeutic index is the lethal dose of a drug for 50 % of the population (LD₅₀) divided by the minimum effective dose for 50 % of the population (ED₅₀).

Therapeutic index or therapeutic ratio = Toxic dose₅₀ / Effective dose₅₀

Lethality is not determined in human clinical trials; instead, the dose that produces toxicity in 50% of the population (TD₅₀) is used to calculate the therapeutic index. Lethal dose is important to determine in animal studies, there are usually severe toxicities that occur at sub-lethal 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 lethal/toxic threshold than the dose taken to elicit the therapeutic effect.

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).

The therapeutic index varies widely among substances, for example, opioid analgesics like Remifentanyl has a therapeutic index of 33,000 : 1 and Tetrahydrocannabinol, a sedative and analgesic of herbal origin has a safe therapeutic index of 1000:1, while Diazepam, and skeletal muscle relaxant has a lower therapeutic index of 100:1. Less-safer drugs such as Digoxin, cardiac glycoside has a therapeutic index of approximately 2:1. Other examples of drugs with a narrow therapeutic range given by FDA which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity are Dimercaprol, Theophylline, Warfarin sodium, Valproic acid, lithium carbonate Clindamycin etc. Most antibiotics, such as the β-lactams, macrolides and quinolones have a wide therapeutic index and therefore do not require therapeutic drug monitoring. Some antibiotics like Gentamycin, Vancomycin, Amphotericin B and Polymyxin B require monitoring to balance efficacy with minimizing adverse effects as they could be irreversible. Other drugs such as Teicoplanin, Flucloxacillin and the antifungal agents like Itraconazole, Flucytosine and Fluconazole are monitored in certain circumstances.

Therefore, it is very important to determine the therapeutic index of the drugs for better administration of the drug minimizing the side effects. It is also important to measure the plasma drug levels as a part of therapeutic drug monitoring to avoid the unnecessary administration of the drug and administration of drugs with narrow therapeutic index with maximum efficiency.

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Written by

Vindhya Marpalli

vindhya.marpalli@clinzen.com