What is a Dose (Biochemistry)?

Introduction

A dose is a measured quantity of a medicine, nutrient, or pathogen which is delivered as a unit. The greater the quantity delivered, the larger the dose. Doses are most commonly measured for compounds in medicine. The term is usually applied to the quantity of a drug or other agent administered for therapeutic purposes, but may be used to describe any case where a substance is introduced to the body. In nutrition, the term is usually applied to how much of a specific nutrient is in a person’s diet or in a particular food, meal, or dietary supplement. For bacterial or viral agents, dose typically refers to the amount of the pathogen required to infect a host.

In clinical pharmacology, dose refers to dosage or amount of dose administered to a person, whereas exposure means the time-dependent concentration (often in the circulatory blood or plasma) or concentration-derived parameters such as AUC (area under the concentration curve) and Cmax (peak level of the concentration curve) of the drug after its administrationneeded]. This is in contrast to their interchangeable use in other fields.

Refer to Defined Daily Dose, Prescribed Baily Dose, Maintenance Dose, and Dosage Form.

Factors Affecting Dose

A ‘dose’ of any chemical or biological agent (active ingredient) has several factors which are critical to its effectiveness. The first is concentration, that is, how much of the agent is being administered to the body at once.

Another factor is the duration of exposure. Some drugs or supplements have a slow-release feature in which portions of the medication are metabolized at different times, which changes the impacts the active ingredients have on the body. Some substances are meant to be taken in small doses over large periods of time to maintain a constant level in the body, while others are meant to have a large impact once and be expelled from the body after its work is done. It’s entirely dependent on the function of the drug or supplement.

The route of administration is important as well. Whether a drug is ingested orally, injected into a muscle or vein, absorbed through a mucous membrane, or any of the other types of administration routes, affects how quickly the substance will be metabolized by the body and thus effects the concentration of the active ingredient(s). Dose-response curves may illustrate the relationship of these metabolic effects.

Medicines

Over-the-Counter Medications

In over-the-counter medicines, dosage is based on age. Typically, different doses are recommended for children 6 years and under, children aged 6 to 12 years, and persons 12 years and older, but outside of those ranges the guidance is slim. This can lead to serial under or overdosing, as smaller people take more than they should and larger people take less. Over-the-counter medications are typically accompanied by a set of instructions directing the patient to take a certain small dose, followed by another small dose if their symptoms don’t subside. Under-dosing is a common problem in pharmacy, as predicting an average dose that is effective for all individuals is extremely challenging because body weight and size impacts how the dose acts within the body.

Prescription Drugs

Prescription drug dosage is based typically on body weight. Drugs come with a recommended dose in milligrams or micrograms per kilogram of body weight, and that is used in conjunction with the patient’s body weight to determine a safe dosage. In single dosage scenarios, the patient’s body weight and the drug’s recommended dose per kilogram are used to determine a safe one-time dose. In drugs where multiple doses of treatment are needed in a day, the physician must take into account information regarding the total amount of the drug which is safe to use in one day, and how that should be broken up into intervals for the most effective treatment for the patient. Medication underdosing occurs commonly when physicians write prescriptions for a dosage that is correct for a certain time, but fails to increase the dosage as the patient needs (i.e. weight based dosing in children, or increasing dosages of chemotherapy drugs if a patient’s condition worsens).

Medical Cannabis

Medical cannabis is used to treat the symptoms of a wide variety of diseases and conditions. The dose of cannabis depends on the individual, the condition being treated, and the ratio of cannabidiol (CBD) to tetrahydrocannabinol (THC) in the cannabis. CBD is a chemical component of cannabis that is not intoxicating and used to treat conditions like epilepsy and other neuropsychiatric disorders. THC is a chemical component of cannabis that is psychoactive. It has been used to treat nausea and discomfort in cancer patients receiving chemotherapy treatment. For anxiety, depression, and other mental health ailments, a CBD to THC ratio of 10 to 1 is recommended. For cancer and neurological conditions, a CBD to THC ratio of 1 to 1 is recommended. The correct dosage for a patient is dependent on their individual reaction to both chemicals, and therefore the dosing must be continually adjusted once treatment is initiated to find the right balance.

There is limited consensus throughout the scientific community regarding the effectiveness of medicinal cannabis.

Cancer

Calculating drug dosages for treatment for more serious diseases like cancer is commonly done through measuring the patient’s body surface area. There are approximately 25 different formulae for measuring a patient’s body surface area, none of them exact. Studies show that selecting the best method for an individual patient is a difficult task; consequently, patient often receive too much or too little medication due to their particular physical anomalies. Therefore, these formulas are typically adjusted by what is known as ‘toxicity-adjusting dosing,’ whereby physicians monitor immune suppression and adjust dosing accordingly. Because this strategy of trial and error requires close monitoring, it is inefficient, risky, and cost ineffective. Research into the development of safer and more accurate dosing methods is ongoing.

Ongoing Research

Another approach that’s been investigated recently is dosing on a molecular level, either through conventional delivery systems, nanoparticle delivery, light-triggered delivery, or other less known/used methods. By combining these drugs with a system that detects the concentration of drug particles in the blood, proper dosing could be achieved for each individual patient. Research in this field was initiated with monitoring of small-molecule cocaine levels in undiluted blood serum with electrochemical aptamer-based sensing. DNA aptamers, which are peptides that have with specific target molecules that they search for, fold in response to the molecule when they find it, and this technology was used in a microfluidic detection system to create an electrochemical signal that physicians can read. Researchers tested it on cocaine detection and found that it successfully found trace amounts of cocaine in blood.

This research was expanded upon and led to the creation of a product called MEDIC (microfluidic electrochemical detector for in vivo continuous monitoring) developed by faculty at the University of California at Santa Barbara. MEDIC is an instrument that can continuously determine the concentrations of different molecules in the blood. The blood does not have to be mixed with anything prior to testing to create a ‘serum’ as the first device did. MEDIC can detect a wide variety of drug molecules and biomarkers. In trials, early models of the device failed after about half an hour because the proteins in whole blood clung to the sensors and clogged the components. This problem was solved via a second chamber that allowed a liquid buffer to flow over the sensors with the blood, without mixing or disturbing the blood, so the results remained unchanged. The device is still in clinical trials and actual implementation in medicine is likely years away, however in the interim, its creators estimate that it could also be used in the pharmaceutical industry to allow for better testing in Phase 3 clinical trials.

Vaccines

Vaccinations are typically administered as liquids and dosed in millilitres. Each individual vaccine comes with constraints regarding at what age they should be administered, how many doses must be given, and over what period of time. There are 15 vaccines that the Centres for Disease Control and Prevention recommend every person (in the United States and Canada) receive between birth and 18 years of age to protect against various infectious agents that may affect long-term health. Most vaccines require multiple doses for full immunity, given in recommended intervals depending on the vaccine. There are several typical vaccination routes:

  • Intramuscular: the needle is inserted perpendicular to the skin into the muscle, beneath the skin and (subcutaneous) tissues that rest on top.
  • Subcutaneous: the needle is inserted at a 45-degree angle into the (subcutaneous) tissue between the outer layer of the skin and the muscle.
  • Intranasal: the vaccine is sprayed into the nose and absorbed through the nasal passage.
  • Oral: the vaccine is swallowed and ingested.

Nutrition

For healthy humans, experts recommend daily intake quantities of certain vitamins and minerals. The Food and Nutrition Board, Institute of Medicine, and National Academy of Sciences sets a recommended Dietary Reference Intake (DRI) in several forms:

  • Recommended Dietary Allowance (RDA): average daily intake which adequately meets the nutrient requirements of 97-98% of healthy individuals.
  • Adequate Intake (AI): established when the evidence gathered for an RDA is inconclusive, An AI is assumed to recommend a daily amount to meet nutritional adequacy.
  • Tolerable Upper Intake Level (UL): maximum amount of a nutrient which can be consumed without causing adverse impacts to an individual’s health.

DRIs are established for elements, vitamins, and macronutrients. Common elemental and vitamin dosages are milligrams per day (mg/d) or micrograms per day (μg/d). Common macronutrient dosages are in grams per day (g/d). Dosages for all three are established by both gender and age.

Individuals take vitamin and mineral supplements to promote healthier lifestyles and prevent development of chronic diseases. There is no conclusive evidence linking continued vitamin and mineral supplement intake with longevity of life.

Infectious Dose

The infectious dose of a pathogen is the number of cells required to infect the host. All pathogens have an infectious dose typically given in number of cells. The infectious dose varies by organism and can be dependent on the specific type of strain. Some pathogens can infect a host with only a few cells, while others require millions or billions.

Examples of infectious doses, ranked loosely in increasing order:

  • Enterohemorrhagic E. coli (causes haemorrhaging of the intestines): 10 bacteria cells.
  • Hepatitis A: 10-100 virus particles.
  • Norovirus (commonly called ‘a stomach bug’): 10-100 virus particles.
  • Rotavirus (severe diarrhoea, can be fatal): 10-100 virus particles.
  • Shigella (shigellosis): 500 bacteria cells.
  • Streptococcus pyogenes (Group A strep throat): 1000 bacteria cells.
  • Salmonella: varies by strain, 100-1 billion bacteria cells.
  • Vibrio cholerae (Cholera): 1000-100,000,000 bacteria cells.

Typically, stomach acids can kill bacteria below the infectious dosing range for a given pathogen and keep the host from feeling symptoms or falling ill. Complexes constructed by fat can protect infectious agents from stomach acid, making fatty foods more likely to contain pathogens that successfully infect the host. For individuals with low or reduced stomach acid concentrations, in infectious dosage for a pathogen will be lower than normal.

Rather than being administered by a physician or individual, infectious dosages are transmitted to a person from other persons or the environment, are generally accidental, and result in adverse side effects until the pathogen is defeated by the individual’s immune system or flushed out of the individual’s system by excretory processes.

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What is a Therapeutic Index?

Introduction

The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug.

It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. The related terms therapeutic window or safety window refer to a range of doses which optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

Classically, in an established clinical indication setting of an approved drug, TI refers to the ratio of the dose of drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50). In contrast, in a drug development setting TI is calculated based on plasma exposure levels.

In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50). Today, more sophisticated toxicity endpoints are used.

For Humans (TD50 / ED50).

For many drugs, there are severe toxicities that occur at sublethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the toxic threshold than the dose taken to elicit the therapeutic effect.

Generally, a drug or other therapeutic agent with a 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.

Terms

  • ED = Effective dose.
  • TD = Toxic dose.
  • LD = Lethal dose.
  • TI = Therapeutic index.
  • TR = Therapeutic ratio.

Therapeutic Index in Drug Development

A high therapeutic index (TI) is preferable for a drug to have a favourable safety and efficacy profile. At early discovery/development stage, the clinical TI of a drug candidate is not known. However, understanding the preliminary TI of a drug candidate is of utmost importance as early as possible since TI is an important indicator of the probability of the successful development of a drug. Recognising drug candidates with potentially suboptimal TI at earliest possible stage helps to initiate mitigation or potentially re-deploy resources.

In a drug development setting, 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 that is more than just a number, 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 with the aim 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 rather than dose for calculating 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 the various aspects of 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.

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 minimise toxicity, include: paracetamol (acetaminophen), dimercaprol, theophylline, warfarin and lithium carbonate.

Some antibiotics and antifungals require monitoring to balance efficacy with minimising adverse effects, including: gentamicin, vancomycin, amphotericin B (nicknamed ‘amphoterrible’ for this very reason), and polymyxin B.

Cancer Radiotherapy

Radiotherapy aims to minimize the size of tumours and kill cancer cells with high energy. The source of high energy arises from x-rays, gamma rays, charged particles and heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is related to the maximum radiation dose by which death of cancer cells is locally controlled and the minimum radiation dose by which cells in normal tissues have low acute and late morbidity. Both of parameters have sigmoidal dose-response curves. Thus, a favourable outcome in dose-response curve is the response of tumour tissue is greater than that of normal tissue to the same dose, meaning that the treatment is effective to tumours and does not cause serious morbidity to normal tissue. Reversely, overlapping response of two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment to tumours. The mechanism of radiation therapy is categorised into direct and indirect radiation. Both direct and indirect radiations induce DNA to have a mutation or chromosomal rearrangement during its repair process. Direct radiation creates a free DNA radical from radiation energy deposition that damages DNA. Indirect radiation occurs from radiolysis of water, creating a free hydroxyl radical, hydronium and electron. Then, hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage base region of DNA.

Cancer cells have imbalance of signals in cell cycle. G1 and G2/M arrest are found to be major checkpoints by irradiation in human cells. G1 arrest delays repair mechanism before synthesis of DNA in S phase and mitosis in M phase, suggesting key checkpoint to lead survival of cells. G2/M arrest occurs when cells need to repair after S phase before the mitotic entry. It was also known that S phase is the most resistant to radiation and M phase was the most sensitive to radiation. p53, a tumour suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle by radiation. For example, irradiation to myeloid leukaemia cell leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with Ataxia telangiectasia delays have hypersensitivity to radiation due to the delay of accumulation of p53.[9] In this case, cells are able to replicate without repair of their DNA, prone to incidence of cancer. Most cells are in G1 and S phase and irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been on focus for therapeutic treatment. Irradiation to a tissue creates response to both irradiated and non-irridiated cells. It was found that even cells up to 50-75 cell diameter distant from irradiated cells have phenotype of enhanced genetic instability such as micronucleation. This suggests the effect of cell-to-cell communication such as paracrine and juxtacrine signalling. Normal cells do not lose DNA repair mechanism whereas cancer cells often lose during radiotherapy. However, the nature of high energy radiation can override the ability of damaged normal cell to repair, leading to cause another risk for carcinogenesis. This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimise dose to normal tissues by altered fractionation. Molecular targeting to DNA repair pathway can lead to radiosensitisation or radioprotection. Examples are direct and indirect inhibitors on DNA double-strand breaks. Direct inhibitors target proteins (PARP family) and kinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target proteins tumour cell signalling proteins such as EGFR and insulin growth factor.

The effective therapeutic index can be affected by targeting, in which the therapeutic agent is concentrated in its area of effect. For example, in radiation therapy for cancerous tumours, shaping the radiation beam precisely to the profile of a tumour in the “beam’s eye view” can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as is done in peptide receptor radionuclide therapy for neuroendocrine tumours and in chemoembolisation or radioactive microspheres therapy for liver tumours and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity.

Safety Ratio

Sometimes the term safety ratio is used instead, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use. In such cases, the effective dose is the amount and frequency that produces the desired effect, which can vary, and can be greater or less than the therapeutically effective dose.

The Certain Safety Factor, also referred to as the Margin of Safety (MOS), is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population (LD1/ED99). This is a better safety index than the LD50 for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another.

Synergistic Effect

A therapeutic index does not consider drug interactions or synergistic effects. For example, the risk associated with benzodiazepines increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone. Therapeutic index also does not take into account the ease or difficulty of reaching a toxic or lethal dose. This is more of a consideration for recreational drug users, as the purity can be highly variable.

Protective Index

The protective index is a similar concept, except that it uses TD50 (median toxic dose) in place of LD50. For many substances, toxic effects can occur at levels far below those needed to cause death, and thus the protective index (if toxicity is properly specified) is often more informative about a substance’s relative safety. Nevertheless, the therapeutic index is still useful as it can be considered an upper bound for the protective index, and the former also has the advantages of objectivity and easier comprehension.

Therapeutic Window

The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include theophylline, digoxin, lithium, and warfarin.

Optimal Biological Dose

Optimal biological dose (OBD) is the quantity of a drug that will most effectively produce the desired effect while remaining in the range of acceptable toxicity.

Maximum Tolerated Dose

The maximum tolerated dose (MTD) refers to the highest dose of a radiological or pharmacological treatment that will produce the desired effect without unacceptable toxicity. The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable adverse health effects in a population, when the level of exposure is not sufficient to cause premature mortality due to short-term toxic effects. The maximum dose is used, rather than a lower dose, to reduce the number of test subjects (and, among other things, the cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing chemical residue tolerances in foods. Maximum tolerated dose studies are also done in clinical trials.

MTD is an essential aspect of a drug’s profile. All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent the prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population.

Patients are often unable to tolerate the theoretical MTD of a drug due to the occurrence of side-effects which are not innately a manifestation of toxicity (not considered to severely threaten a patients health) but cause the patient sufficient distress and/or discomfort to result in non-compliance with treatment. Such examples include emotional “blunting” with antidepressants, pruritus with opiates, and blurred vision with anticholinergics.