Tag: PDD: Prescribed Daily Dose

What is a Dose (Biochemistry)?

Published on by Andrew Marshall1 Comment

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.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Dose_(biochemistry) >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is a Maintenance Dose?

Published on by Andrew Marshall4 Comments

Introduction

In pharmacokinetics, a maintenance dose is the maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state.

Refer to Defined Daily Dose, Prescribed Daily Dose, and Average Daily Quantity.

Outline

This is not to be confused with dose regimen, which is a type of drug therapy in which the dose [mg] of a drug is given at a regular dosing interval on a repetitive basis. Continuing the maintenance dose for about 4 to 5 half lives (t½) of the drug will approximate the steady state level. One or more doses higher than the maintenance dose can be given together at the beginning of therapy with a loading dose.

A loading dose is most useful for drugs that are eliminated from the body relatively slowly. Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate level, but this also means that, without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level.

Calculating the Maintenance Dose

The required maintenance dose may be calculated as:

Cp CL divided by F = MD

Where:

  • MD = the maintenance dose rate [mg/h].
  • Cp = desired peak concentration of drug [mg/L].
  • CL = clearance of drug in body [L/h].
  • F = bioavailability.

For an intravenously administered drug, the bioavailability (F) will equal 1, since the drug is directly introduced to the bloodstream. If the patient requires an oral dose, bioavailability will be less than 1 (depending upon absorption, first pass metabolism etc.), requiring a larger loading dose.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Maintenance_dose >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Prescribed Daily Dose?

Published on by Andrew Marshall4 Comments

Introduction

Prescribed daily dose (PDD) is the usual dose of medication calculated by looking at a group of prescriptions for the medication in question.

At times the PDD needs to be related to the condition being treated.

Refer to Defined Daily Dose, Average Daily Quantity, and Maintenance Dose.

What is Defined Daily Dose?

Published on by Andrew Marshall5 Comments

Introduction

The defined daily dose (DDD) is a statistical measure of drug consumption, defined by the World Health Organisation (WHO) Collaborating Centre for Drug Statistics Methodology (WHOCC).

It is defined in combination with the ATC Code drug classification system for grouping related drugs. The DDD enables comparison of drug usage between different drugs in the same group or between different health care environments, or to look at trends in drug utilisation over time. The DDD is not to be confused with the therapeutic dose or prescribed daily dose (PDD), or recorded daily dose (RDD), and will often be different to the dose actually prescribed by a physician for an individual person.

The WHO’s definition is: “The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.” The Defined Daily Dose was first developed in the late 1970s.

Refer to Prescribed Daily Dose, Average Daily Quantity, and Maintenance Dose.

Assignment

Before a DDD is assigned by the WHOCC, it must have an ATC Code and be approved for sale in at least one country. The DDD is calculated for a 70kg adult, except if this drug is only ever used in children. The dose is based on recommendations for treatment rather than prevention, except if prevention is the main indication. Generally there is only one DDD for all formulations of a drug, however exceptions are made if some formulations are typically used in significantly different strengths (e.g. antibiotic injection in a hospital vs tablets in the community). The DDD of combination tablets (containing more than one drug) is more complex, most taking into account a “unit dose”, though combination tablets used for high blood pressure take the number of doses per day into account.

The formula for determining the dose is:

  • If there is a single recommended maintenance dose in the literature, this is preferred.
  • :If there are a range of recommended maintenance doses then
    • If the literature recommends generally increasing from initial to maximum dose provided it is tolerated, pick the maximum dose.
    • If the literature recommends only increasing from an initial dose if not sufficiently effective, pick the minimum dose.
    • If there is no guidance then pick the mid point between the dose range extremes.

The DDD of a drug is reviewed after three years. Ad hoc requests for change may be made but are discouraged and generally not permitted unless the main indication for the drug has changed or the average dose used has changed by more than 50%.

Limitations

The DDD is generally the same for all formulations of a drug, even if some (e.g. flavoured syrup) are designed with children in mind. Some types of drug are not assigned a DDD, for example: medicines applied to the skin, anaesthetics and vaccines. Because the DDD is a calculated value, it is sometimes a “dose” not actually ever prescribed (e.g. a midpoint of two prescribed tablet strengths may not be equal to or be a multiple of any available tablet). Different people may in practice be prescribed higher or lower doses than the DDD, for instance in children, people with liver or kidney impairment, patients with a combination therapy, or due to differences in drug metabolism between individuals or ethnicities (genetic polymorphism).

Although designed primarily for drug utilisation research, data using the DDD can only give a “rough estimate” compared with actually collecting statistics on drug use in practice. The DDD is often use for long term research and analysis of drug utilisation trends over time, so changes to the DDD are avoided if possible, whereas changes in the actual daily dose prescribed for a population may often occur. For example, the Recorded Daily Dose (RDD) of simvastatin in Canada in 1997 was only 8% different to the DDD, but by 2006 it was 67% different. In 2009, the DDD of several statins were updated, with simvastatin changing from 15mg to 30mg.

The DDD is based on the maintenance dose, but in practice patients in a population will be on a mix of initial and maintenance doses.

Use and Misuse

The DDD can be used as the basis for calculating various indicators of drug utilisation. The indicator DDD per 1000 inhabitants per day can suggest what portion of a population are regularly using a drug or class of drugs. The indicator DDD per 100 bed days estimates on average how many inpatients are given a drug every day in hospital. The indicator DDDs per inhabitant per year can be used for drugs normally prescribed for short treatment duration (e.g. antibiotics) to indicate the average number of days in a year a person may take that treatment. The extent to which estimates using DDD reflect actual clinical practice depends on how close the DDD is to the typical prescribed dose in that country or setting and at that point in history.

Because the primary purpose of the ATC/DDD system is drug consumption measurement, the WHO recommend caution when considering its use for cost analysis: “DDDs, if used with caution can be used to compare, for example, the costs of two formulations of the same drug.” So, the cost per DDD of an extended-release tablet taken once a day compared with a standard tablet taken twice a day, may indicate the extended-release tablet costs much more to treat the same condition.

In contrast, using DDD to compare the cost of different drugs or drug groups is “usually not valid” according to the WHO. They recommend that “DDDs are not suitable for comparing drugs for specific, detailed pricing, reimbursement and cost-containment decisions”. The DDD may not necessarily compare well with the actual PDD, and two drugs in the same ATC group may not be equally effective at their DDD.

For example, an analysis of statin use in the Ontario Drug Benefit Programme, 2006-2007. The average cost per DDD of rosuvastatin was 21% more expensive than atorvastatin ($1.14 compared to $0.94), which would suggest the shift at the time from prescribing atorvastatin to prescribing rosuvastatin would result in increased costs to the healthcare budget. Both had a DDD at that time of 10mg, but 10mg was not the only dose prescribed. For example, atorvastatin once daily at 10mg, 20mg, 40mg and 80mg was prescribed 45%, 36%, 16% and 3% of the time respectively. If one compared cost per unit (daily tablet) then rosuvastatin was instead 24% cheaper than atorvastatin ($1.44 vs $1.90), and if one compares cost per RDD (recorded daily dose) then rosuvastatin was 26% cheaper than atorvastatin ($1.43 vs $1.93). An erroneous conclusion of a healthcare budget cost increase arises in this case from using cost per DDD. At the time, the RDD of rosuvastatin was similar to its DDD (12.6 mg vs 10mg), but the RDD of atorvastatin was twice its DDD (20.6 mg vs 10mg). The DDD of atorvastatin was revised in 2009 to 20mg.

The Canadian Patented Medicine Prices Review Board analysed the use of DDD for drug utilisation and cost analysis and offered recommendations. They particularly concentrated on the problems that occur when the RDD observed in the population deviates more than minimally from the DDD. They conclude that the DDD methodology “should generally not be used to interpret Canadian drug utilisation; should generally not be applied in cost analyses; and should generally not be applied in policy decisions”. The Board recommend that provided the agreement between DDD and RDD is known and minimal, then a cost per DDD “can provide a rough idea of the treatment cost” but “caution should still be used, as misinterpretation of the results based on the DDD methodology may still occur”. If the agreement between DDD and RDD is unknown or a significant disagreement is known, then the DDD methodology “should not be used in cost analyses”. In all cases, the Board state “The DDD methodology should not be used in guiding policy decisions regarding reimbursement, therapeutic substitution and other pricing decisions”.

Example

If the DDD for a certain drug is given, the number of DDDs used by an individual patient or (more commonly) by a collective of patients is as follows.

Drug usage (in DDDs) = (Items issued x Amount of drug per item) divided by DDD.

For example, the analgesic (pain reliever) paracetamol has a DDD of 3 g, which means that an average patient who takes paracetamol for its main indication, which is pain relief, uses 3 grams per day. This is equivalent to six standard tablets of 500 mg each. If a patient consumes 24 such tablets (12 g of paracetamol in total) over a certain span of time, this equals a consumption of four DDDs.

Drug usage in DDDs = (24 (items) x 500 (mg/item)) divided by 3000 mg = 4

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Defined_daily_dose >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.