potentially re-deploy resources. TI is the quantitative relationship between efficacy (pharmacology) and safety (toxicology), without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI to something useful, the nature and limitations of pharmacological and/or toxicological endpoints must be considered. Depending on the intended clinical indication, the associated unmet medical need and/or the competitive situation, more or less weight can be given to either the safety or efficacy of a drug candidate in order to create a well balanced indication-specific safety vs efficacy profile. In general, it is the exposure of a given tissue to drug (i.e. drug concentration over time), rather than dose, that drives the pharmacological and toxicological effects. For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors. These considerations emphasize the importance of using exposure instead of dose to calculate TI. To account for delays between exposure and toxicity, the TI for toxicities that occur after multiple dose administrations should be calculated using the exposure to drug at steady state rather than after administration of a single dose. A review published by Muller and Milton in Nature Reviews Drug Discovery critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics. Range of therapeutic indices The therapeutic index varies widely among substances, even within a related group. For instance, the opioid painkiller remifentanil is very forgiving, offering a therapeutic index of 33,000:1, while Diazepam, a benzodiazepine sedative-hypnotic and skeletal muscle relaxant, has a less forgiving therapeutic index of 100:1. Morphine is even less so with a therapeutic index of 70. Less safe are cocaine (a stimulant and local anaesthetic) and ethanol (colloquially, the "alcohol" in alcoholic beverages, a widely available sedative consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively. Paracetamol, known by its trade name Tylenol, also has a therapeutic index of 10. Even less safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1. Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include dimercaprol, theophylline, warfarin and lithium carbonate. Some antibiotics and antifungals require monitoring to balance efficacy with minimizing adverse effects, including: gentamicin, vancomycin, amphotericin B (nicknamed 'amphoterrible' for