Research Paper E-ISSN NO : 2455-295X | VOLUME : 2 | ISSUE : 11 | NOV 2016 POSOLOGICAL DOSE OF THERAPEUTICS OVER PROPHYLAXIS IN TOXICOLOGICAL SERENDIPITY Kinsuk Sarker 1 | Apurbo Sarker 2 | Arittra Ghosh 3 | Prof. Dr. Dhrubo Jyoti Sen 4 1 Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana–384001, Gujarat, India. ABSTRACT Drug, any chemical substance that affects the functioning of living things and the organisms (such as bacteria, fungi and viruses) that infect them. Pharmacology, the science of drugs, deals with all aspects of drugs in medicine, including their mode of action, physical and chemical properties, metabolism, therapeutics and toxicity. The therapeutic index of a drug is the ratio between the dosage that causes a toxic/lethal effect and the dosage that causes a therapeutic effect. The term pharmacotherapy refers to the use of drugs for treating diseases, whereas pharmacology is the study of drug action on living systems. It is the interaction of the drug molecules and drug receptors that brings about a therapeutic effect. However, it is extremely essential to administer the drug in the right dose to achieve such an effect. If taken in large doses, certain drugs could cause adverse effects. Thus, in order to reap the benefits, it is essential to assess the right dose. Therapeutic drug monitoring (TDM) becomes essential to determine the dose at which a drug will be safe and effective, especially with those with a narrow therapeutic index (NTI). Also, monitoring might be required when the patient is affected by a medical condition that has an adverse effect on the clearance of NTI drugs. There's no denying the fact that drug metabolism could vary from person to person. Thus, the key to avoid drug-related problems is to consider the drug's therapeutic index and other relevant factors for ensuring safety. Therapeutic index (TI) refers to any of the several indices that are used for measuring a drug's safety. The most common TI is the ratio of the median lethal dose to the median effective dose of a drug. The formula for TI is: LD50/ED50. LD50 stands for median lethal dose and ED50 stands for median effective dose (therapeutic dose). LD50 refers to the dose that would produce a lethal effect in 50% of the population, whereas ED50 refers to the dose that will produce the desired therapeutic effect in 50% of the population. This index is commonly used to measure a drug's safety. The therapeutic index formula is: TD50/ED50. TD50 stands for the median toxic dose, whereas ED50 stands for the median effective dose. TD50 refers to the minimum drug dose that would produce a toxic effect in 50% of the population, whereas ED50 refers to the minimum drug dose that will produce the desired therapeutic effect in 50% of the population. Another related concept is that of therapeutic range (TR). TR is the range of doses/concentrations at which a therapeutic agent or drug produces a therapeutic response without causing any significant adverse effect in patients. It can be measured by: MEC/MTC. MEC stands for minimum effective concentration, whereas MTC stands for minimum toxic concentration. MEC is the minimum concentration of the drug that is required for achieving the therapeutic effect, whereas MTC is the minimum concentration at which toxicity occurs. Basically, if at a particular dosage, a drug is above MTC, it would cause adverse effects. Similarly, a drug below MEC will not produce the desired therapeutic response. Keywords: TDM, NTI, TI, ED50, ED95, LD50, ID50, IC50, TD50, LDLo, MEC, MTC, TD, TR, USFDA, OBD, MTD, Safety Ratio, USFDA, Protective index, Therapeutic window. on plasma exposure levels. In the early days of pharmaceutical INTRODUCTION toxicology, TI was frequently determined in animals as lethal A ratio that compares the blood concentration at which a drug dose of a drug for 50% of the population (LD50) divided by the becomes toxic and the concentration at which the drug is minimum effective dose for 50% of the population (ED50). effective is known as therapeutic index (TI). The larger the Today, more sophisticated toxicity endpoints are used.[1] therapeutic index (TI), the safer the drug is. If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity. The therapeutic index (TI) (also referred to as therapeutic window or safety window or sometimes as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. Figure-1: Therapeutics and Prophylaxis Classically, in an established clinical indication setting of an Therapeutic Index=LD /ED in animal studies, or for humans, approved drug, TI refers to the ratio of the dose of drug that 50 50 Therapeutic Index=TD /ED . For many drugs, there are causes adverse effects at an incidence/severity not compatible 50 50 severe toxicities that occur at sub-lethal doses in humans and with the targeted indication (e.g. toxic dose in 50% of subjects, these toxicities often limit the maximum dose of a drug. A TD ) to the dose that leads to the desired pharmacological 50 higher therapeutic index is preferable to a lower one: a patient effect (e.g. efficacious dose in 50% of subjects, ED ). In 50 would have to take a much higher dose of such a drug to reach contrast, in a drug development setting TI is calculated based INTERNATIONAL EDUCATIONAL SCIENTIFIC RESEARCH JOURNAL 61 Research Paper E-ISSN NO : 2455-295X | VOLUME : 2 | ISSUE : 11 | NOV 2016 the toxic threshold than the dose taken to elicit the therapeutic the term in this regard would be ED50 of 95%. Notwithstanding, [4] effect. Generally, a drug or other therapeutic agent with a usage of the term ED95 has stuck in this context. narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of the actual blood levels achieved in the person taking it. This may be achieved through therapeutic drug monitoring (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with lithium due to its narrow therapeutic range.[2] An effective dose (ED) in pharmacology is the dose or amount of drug that produces a therapeutic response or desired effect in some fraction of the subjects taking it. ED=Effective Dose, TD=Toxic Dose, LD=Lethal Dose, TI=Therapeutic Index, TR=Therapeutic Ratio. Figure-2: Graphical plot of therapeutic index EFFECTIVE DOSE50: It has been stated that any substance MEDIAN TOXIC DOSE: In toxicology, the median toxic can be toxic at a high enough dose. The line between efficacy dose (TD50) of a drug or toxin is the dose at which toxicity and toxicity is dependent upon the particular patient, although occurs in 50% of cases. The type of toxicity should be specified the dose administered by a physician should fall into the for this value to have meaning for practical purposes. The predetermined therapeutic window of the drug. The importance median toxic dose encompasses the category of toxicity that is of determining the therapeutic range of a drug cannot be greater than half maximum effective concentration (ED50) but overstated. This is generally defined by the range between the less than the median lethal dose (LD50). However, for some minimum effective dose (MED) and the maximum tolerated highly potent toxins (ex. lofentanil, botulinum toxin) the dose (MTD). The MED is defined as the lowest dose level of a difference between the ED50 and TD50 is so minute that the pharmaceutical product that provides a clinically significant values assigned to them may be approximated to equal doses. response in average efficacy, which is also statistically Since toxicity need not be lethal, the TD50 is generally lower significantly superior to the response provided by the placebo. than the median lethal dose (LD50) and the latter can be Similarly, the MTD is the highest possible but still tolerable considered an upper bound for the former. However, since the dose level with respect to a pre-specified clinical limiting toxicity is above the effective limit, the TD50 is generally toxicity. In general, these limits refer to the average patient greater than the ED50. If the result of a study is a toxic effect that population. For instances in which there is a large discrepancy does not result in death, it is classified as this form of toxicity. between the MED and MTD, it is stated that the drug has a large Toxic effects can be defined differently, sometimes considering therapeutic window. Conversely, if the range is relatively the therapeutic effect of a substance to be toxic (such as with small, or if the MTD is less than the MED, then the chemotherapeutics) which can lead to confusion and contention pharmaceutical product will have little to no practical value. regarding a substance's TD50. Examples of these toxic The "median effective dose" is the dose that produces a quantal endpoints include cancer, blindness, anemia, birth defects, etc. effect (all or nothing) in 50% of the population that takes it Alternative definition: ED95 (when referring to non (median referring to the 50% population base). It is also depolarizing muscle relaxants) is the ED50 from a cumulative sometimes abbreviated as the ED , meaning effective dose, for log dose response curve where the quantum is a 95% reduction 50 in twitch height.[5] 50% of people receiving the drug. The ED50 is commonly used as a measure of the reasonable expectancy of a drug effect, but LETHAL DOSE: In toxicology, the lethal dose (LD) is an does not necessarily represent the dose that a clinician might indication of the lethality of a given substance or type use.