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APHE Anatomy, Physiology, and Health Education

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# Steps of drug development (cont'd...)

## Number needed to treat (NNT)

The NNT is the average number of patients who need to be treated to prevent one additional bad outcome. The NNT determination is done in clinical trial setting. The harmful or beneficial effect of the test group is compared with the control group [Rang MP et. al., 2007].

### Detremination of NNT

Group A patients are given test drug for a known period and group B keeps untreated (control); the probability of appearance of a particular toxicity for a defined end point (say 3 years) among the patients of A group is pA (probability of still having the disease after taking the pill ) and the probability of appearance of a particular toxicity for a defined end point among the patients of B group is pB (probability of still having the disease even though one didn't take the pill) and, then the absolute risk reduction= (pB - pA) and NNT is $1/(pB - pA)$. NNT is a number between 1 and infinite. The drug is considered to be the safest if the NNT is 1, where everyone improves with treatment and no one improves with control. The higher the NNT, the less effective is the treatment. If the number comes with negative value, it is not taken into account and called number needed to harm (NNH) [Rang MP et. al., 2007, Nuovo J et. al., 2002].

Table. 2. Representation of safety margin of drugs, based on NNT

 Catagory of drug pA pB NNT Prefect drug 0 1.0 1.0 Very good drug 0.1 0.9 1.25 Satisfactory drug 0.3 0.7 2.5 High placebo effect 0.4 0.5 10 Low cure rate 0.8 0.9 10 Go away by itself 0.1 0.2 10 Subotages cure 0.9 0.8 -10 (number needed to harm)

If there is possibility of repeated dosing of the drug (depend upon the disease), then the acute toxicity study is not sufficient to determine the safety margin of the drug and sub acute (28 days), sub chronic (90 days) and chronic toxicity (12-24 months) tests are done in such cases, depending upon the probable use of the molecule. In case of the drug is intended to be used for long term, the effect of the drug on fertility and fetal development is also evaluated on this step [Rang MP et. al., 2007].

### Subacute/ subchronic/chronic toxicity tests

It is defined by the GHS as, specific target organ/systemic toxicity, arises due to repeated exposure to the drug. The animals are given a specific dose every day for 28 days (sub acute) or 90 days (sub chronic) or 12-24 months (chronic) and monitored every day for any signs and symptoms of toxicity. On the consecutive day, the animals are sacrificed and observed any changes in haematological profiling, biochemical profiling and histopathological changes of any organs. There are two probable outcomes, no observable adverse drug effects or adverse drug effects in a benchmark dose. In later case, another dose is fixed in case of chronic use of the drug, if ED50 permits. Otherwise, the molecule is removed from the study in this step. To evaluate the genotoxicity, the study is done in two species. [Rang MP et. al., 2007, Bogdan T].

### ii. Pharmacokinetic study

After the therapeutic dose of the lead is fixed from previous step, it is applied on the laboratory animals to evaluate the absorption, distribution (amount of drug, present in plasma/tissue or protein binding nature of the drug etc.), metabolism or biotransformation (chemical alteration of the drug in the body) and excretion (removal of the drug from system, after desired therapeutic effect) [Rang MP et. al., 2007].

### ii. Pharmacokinetic study

After the therapeutic dose of the lead is fixed from previous step, it is applied on the laboratory animals to evaluate the absorption, distribution (amount of drug, present in plasma/tissue or protein binding nature of the drug etc.), metabolism or biotransformation (chemical alteration of the drug in the body) and excretion (removal of the drug from system, after desired therapeutic effect) [Rang MP et. al., 2007].

#### Reference

[Rang MP et. al., 2007] Rang HP, Dale MM, Ritter J M, Moore P K, Pharmacology, 5th Edition, Elsevier, 2-752, 2007.
[Bogdan T] Bogdan T, George F, Leon M, Radu I, Chapter 15: Determination of drug toxicity in animals, Experimental model in rodents, 231-260.