What Is the Therapeutic Index?

Therapeutic index (TI) is an indicator of drug safety. The ratio of the half lethal dose (LD50) to the half effective dose (ED50) is usually referred to as the therapeutic index. But the therapeutic index does not fully reflect the safety of the drug.

Therapeutic index (TI) is an indicator of drug safety. The ratio of the half lethal dose (LD50) to the half effective dose (ED50) is usually referred to as the therapeutic index. But the therapeutic index does not fully reflect the safety of the drug.

Chinese name

Therapeutic index

Foreign name

therapeutic index

Short name

TI

Use

Drug safety indicators

Treatment Index I. Definition

Therapeutic index refers to the ratio of half lethal dose (LD50) to half effective dose (ED50).

Therapeutic Index II. Calculation Formula

TI = LD50 / ED50

Therapeutic index III. Calculation method

Generally, the treatment index is calculated by measuring the half lethal dose (LD50) and the half effective dose (ED50). The methods for measuring the half lethal dose (LD50) and half effective dose (ED50) are as follows:

1. Kou's method Kauber's method (Karber's method) was proposed by KARBER in 1931, because it was complicated to calculate, it was not widely popular at that time. In 1963, Sun Ruiyuan designed a reasonable experiment, improved and developed the Kou's method, and simplified its calculation. In terms of simplicity, it is better than the cumulative method and the Koch method, and it also improves the accuracy compared with the Koch method. The calculation result is very close to the Bliss probability unit method. In 1974, Yang Shihong further simplified his calculation process, reduced the amount of calculation, and derived a new formula. In practical application, because the Kou's method and its improved method are calculated directly according to the formula according to the results, there is no need to make various modifications because the data is inaccurate, eliminating other more complicated statistical calculations. The calculation results are accurate and the standard error can be obtained, but only three conditions must be met when applied: the reaction volume is approximately normally distributed; the dose must be distributed in an equal series; the number of animals in each group is equal. Although there are conditions, there are still many researchers who reasonably design experiments to be able to use this method for calculations ^[1] .

2. Cumulative method Cumulative method, also known as Reed-Muench method, is an experiment in which doses are arranged in equal series, and the number of animals in each group is equal. It sums up the number of experimental dead animals and surviving animals first, and then uses the data of the sum to calculate the mortality. The accumulation method is convenient to calculate and is more commonly used in microbiology, especially in dilution analysis; but the biggest disadvantage of this method is that it does not consider operating errors and has an "approximation", which makes the calculation result inaccurate and can only be used as a rough judgment .

3. Weighting method Weighting method, also known as Bliss method, is the most accurate and reliable measurement method at present. Because of its rigorous precision in mathematics, it is even called the normal method of probability unit. In the early days, it was difficult to generalize because its calculation process was too cumbersome. With the popularity of computers, researchers are increasingly using calculation programs based on the Bliss method. In 1988, Chinese scholars began to perform calculations on Apple computers using the Basic language.

4. Horn's method Horn's method is also called visual diagram method. Like the statistical idea of the regression line method, all kinds of data that can be converted into geometrically regular patterns can be used. Horn's method draws a line directly on the graph paper based on experimental data. The linear regression method is more accurate than the visual inspection method, but the corresponding calculation is large. These two methods are simple and easy to use and save animals. The disadvantage is that the confidence limits of the obtained values are large and not accurate enough. However, after many years of practical application and verification, the results obtained by the same test substance are very similar to those obtained by the Kou's method. Therefore, the measurement results should be considered credible and valid. The visual method can directly calculate the value using the probability unit-logarithmic paper, without having to check the logarithmic table and the response rate-probability unit table, thereby making the calculation easier.

5. Sequential method Sequential method derives its name from a book of the same name published by WALD in 1948. Its research object is sequential sampling schemes and how to use the samples obtained from such sampling schemes to make statistical inferences. The main calculation principle is to estimate the value by the number of negative and positive reactions. UDP consists of a limit test and a main test. It is required to concentrate the dose above and below the 50% response rate, which can save experimental animals. The method is to select a series of doses arranged in equal series, and the animals are sequentially tested one by one. That is, a dose of nearly 50% response rate is obtained through preliminary experiments, and the number of experiments is calculated at this time. When a negative reaction occurs in the animal, a higher dose is given to the next animal; when a positive reaction occurs in the animal, a lower dose is given to the next animal. The total number of valid animals required for the experiment, n, should be determined before the experiment begins. The operation is more convenient, saves animals, can observe the toxicity performance, and obtain the corresponding confidence interval. The amount of test substance required is small; however, the experimental dose requirements are arranged in the same order, and the error cannot be obtained. The results obtained by different treatments were tested for significance.

6. Fixed dose method (FDP) FDP was proposed by the British Toxicology Society in 1984. After the Brussels agreement, the European Commission funded a comparative study of the old and new methods for the acute toxicity test of 20 compounds in 33 laboratories in the world. The consistency rate of toxicity classification was 87.2%. It can provide sufficient data for risk assessment, including the nature of poisoning, the time, duration and experimental results of poisoning.

Therapeutic index IV. Therapeutic index and drug safety

The therapeutic index does not fully reflect the safety of the drug.

The half effective dose (50% effective dose, ED50) refers to the dose that can cause 50% of the maximum response intensity in the quantity response, and refers to the dose that causes 50% of the subjects to have a positive response in the qualitative response. By analogy, if the effect is convulsions or death, it is called 50% convulsion or 50% lethaldose (LD50). The smaller the ED50 of a drug, the larger the LD50 means that the drug is safer. Generally, the ratio of the LD50 to the ED50 of a drug is often referred to as the therapeutic index to indicate the safety of the drug. However, if the dose-response curve of a drug is not parallel to its dose toxicity curve, the TI value cannot fully reflect the safety of the drug, so some people use the distance between LD5 and ED95 or LD1 and ED99 to indicate the safety of the drug. Therefore, it is more reliable to use the therapeutic index and safety range to indicate the safety of the drug ^[2] .