Median toxic dose

Hunt et al. [6] demonstrated that the DTI is also equivalent to the ratio of the therapeutic index (abbreviated to TI in Hunt et al. s paper in this chapter TI is defined differently, see Section 13.4.3) of the drug-carrier conjugate and that of the free drug. The therapeutic index (also called the therapeutic ratio) is a statistical measure defined as the ratio of the median toxic dose to the median effective dose [22]. 

ED 50 the median effective (therapeutic) dose - units of mg/kg body weight LDso the median lethal (fatal) dose - units of g/kg, mg/kg, mg/kg LCso the median lethal concentration - units of ppm, mg/L TDso tile median toxic dose... 

FIGURE 1-4 Cumulative dose-response curve. The median effective dose CED5tl) is 10 mg, and the median toxic dose (TD50] is 320 mg. The therapeutic index (Tf) for this drug is 32. 

It should be noted, however, that the TI is a relative term. Acetaminophen, a nonprescription analgesic, has a TI of approximately 27 (i.e., the ratio of the median toxic dose to the median effective dose equals 27). Prescription agents tend to have lower TIs. For instance, the narcotic analgesic meperidine (Demerol)... 

Median toxic dose (ABBR TD o) The drug dose that produces a specific adverse (toxic) response in 50 percent of the patients in whom it is tested. 

Therapeutic index (ABBR TI) A ratio used to represent the relative safety of a particular drug the larger the therapeutic index, the safer the drug. It is calculated as the median toxic dose divided by the median effective dose. (In animal trials, the median lethal dose is often substituted for the median toxic dose.)... 

Moeller, R., Puschner, B., Walker, R., Rocke, T., Galey, F., Cullor, J., Ardans, A. (2003). Determination of the median toxic dose of type C. botulinum toxin in lactating dairy cows. J. Vet. Diagn. Invest. 15 523-6. 

As shown in Figure 1-2-5, these D-R curves can also be used to show the relationship between dose and toxic effects of a drug. The median toxic dose of a drug (TD50) is the dose that causes toxicity in 50% of a population. 

Consequently, drug design should focus not on increasing activity alone, but on increasing the therapeutic index (TI). This index reflects the degree of selectivity or margin of safety. It is usually defined as the ratio between the median toxic dose (TDgo) and the median effective dose (ED ) ... 

Therapeutic index The relative measure of a drug s toxicity or safety level the difference between the median effective dose the median toxic dose the safety margin of a drug. 

The median effective dose of a drug is that quantity that will produce 50% of the desired therapeutic intensity. The median toxic dose is that quantity of drug that will produce a defined toxic effect in 50% of the individuals tested. The relationships between the desired and undesired effects of a drug are expressed as its therapeutic index. It is defined as the ratio between a drug s median toxic dose and its median effective dose (TDSO/EDSO). 

See Section 5.3.3 for chronic toxicity study design. The TD50 is the median toxic dose, which is defined as the dose of a test chemical, administered repeatedly, usually daily, that results in the manifestation of the specified toxic endpoint in half of the test animals within the time frame of the study, e.g., the adult life span of the test animal. As is the case with acute toxicity, the route of exposure and the test species also have a significant effect on the dose of a chemical causing chronic toxicity, and they are reported with the TDjq. 

Consequently, the main goal of drug design should be not just to increase the activity, but to increase the therapeutic index (77) as well. This index is usually defined as the ratio between median toxic dose (TD o) and median effective dose (EDso) ... 

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