Therapeutic Index

Abstract

Therapeutic index is an expression of the relative toxicity as compared to efficacy of a given compound. In animal studies, it can be computed as the ratio of the median lethal dose (LD 50 ) to the median effective dose (ED 50 ). In humans, it is frequently expressed as the ratio of the median toxic dose (TD 50 ) to the ED 50 . Several issues limit the utility of the therapeutic index, and to‐date there remains no official list of drugs considered to possess narrow therapeutic indices. Mortality is a poor measure of a drug's toxicity and raises ethical concerns in animal studies. Similarly, ED 50 can be a poor measure of a drug's effectiveness because of lack of consistency in endpoint biomarkers and because the ED 50 may be different for multiple conditions the drug may be used to treat. When LD 50 and ED 50 are obtained in animals, any extrapolation to humans is limited. In addition, multiple factors of interindividual and intraindividual variability exist in humans and can limit the utility of a therapeutic index estimate. Interindividual variability can be caused by either pharmacokinetic or pharmacodynamic differences, and may play an important role in brand‐to‐generic switching of narrow therapeutic index drugs. Intraindividual variability can also be related to physiologic factors that affect absorption, distribution, metabolism, or excretion of a drug. In conclusion, use of a therapeutic index requires an understanding of its limitations, and may be most useful in the preclinical stages of drug testing where limited experience of the drug's administration is available. To date, there remains no official guidance to research laboratories and pharmaceutical companies on the optimal use of therapeutic index.

Engineered Ultrasmall Nanoparticle Drug‐Immune Conjugates with “Hit and Run” Tumor Delivery to Eradicate Gastric Cancer

“…The TI can be a useful indicator, albeit controversial in terms of its significance, and reflects the selectivity of a drug to elicit the desired effect rather than a toxic one. [ 76 ]…”

Remimazolam: its clinical pharmacology and evolving role in anesthesia and sedation practice

“…Another study examined that the 50 and 95% effective doses (ED50 and ED95, respectively) for patients with respiratory arrest were 0.11–0.25 and 0.20–0.47 mg/kg, respectively, while the ED50 and ED95 for patients with an MOAA/S score of less than 2 were 0.08–0.19 and 0.14–0.33 mg/kg, respectively. When an MOAA/S score of less than 2 and respiratory arrest are defined as effective and toxic, respectively, the therapeutic index [27] for respiratory arrest versus a MOAA/S score of less than 2 is less than 1.5, which is considered a low therapeutic index in most clinical arenas. The median effect-site concentrations for MOAA/S scores of 1 and 3 were 0.64 and 0.48 μg/ml, respectively [21 ▪▪ ].…”