What is a Maintenance Dose?

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?

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?

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.

What is the Anatomical Therapeutic Chemical Classification System?

Introduction

The Anatomical Therapeutic Chemical (ATC) Classification System is a drug classification system that classifies the active ingredients of drugs according to the organ or system on which they act and their therapeutic, pharmacological and chemical properties.

Its purpose is an aid to monitor drug use and for research to improve quality medication use. It does not imply drug recommendation or efficacy. It is controlled by the World Health Organisation Collaborating Centre for Drug Statistics Methodology (WHOCC), and was first published in 1976.

Brief History

The ATC system is based on the earlier Anatomical Classification System, which is intended as a tool for the pharmaceutical industry to classify pharmaceutical products (as opposed to their active ingredients). This system, confusingly also called ATC, was initiated in 1971 by the European Pharmaceutical Market Research Association (EphMRA) and is being maintained by the EphMRA and Intellus. Its codes are organised into four levels. The WHO’s system, having five levels, is an extension and modification of the EphMRA’s. It was first published in 1976.

Coding System

This pharmaceutical coding system divides drugs into different groups according to the organ or system on which they act, their therapeutic intent or nature, and the drug’s chemical characteristics. Different brands share the same code if they have the same active substance and indications. Each bottom-level ATC code stands for a pharmaceutically used substance, or a combination of substances, in a single indication (or use). This means that one drug can have more than one code, for example acetylsalicylic acid (aspirin) has A01AD05 (WHO) as a drug for local oral treatment, B01AC06 (WHO) as a platelet inhibitor, and N02BA01 (WHO) as an analgesic and antipyretic; as well as one code can represent more than one active ingredient, for example C09BB04 (WHO) is the combination of perindopril with amlodipine, two active ingredients that have their own codes (C09AA04 (WHO) and C08CA01 (WHO) respectively) when prescribed alone.

The ATC classification system is a strict hierarchy, meaning that each code necessarily has one and only one parent code, except for the 14 codes at the topmost level which have no parents. The codes are semantic identifiers, meaning they depict information by themselves beyond serving as identifiers (namely, the codes depict themselves the complete lineage of parenthood). As of 07 May 2020, there are 6,331 codes in ATC; the table below gives the count per level.

ATC LevelCodesDifferent Names/Pharmaceuticals
11414
29494
3267262
4889819
550674363

Classification

In this system, drugs are classified into groups at five different levels.

First Level

The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:

CodeContents
AAlimentary tract and metabolism
BBlood and blood forming organs
CCardiovascular system
DDermatologicals
GGenito-urinary system and sex hormones
HSystemic hormonal preparations, excluding se hormones and insulins
JAnti-infectives for systemic use
LAntineoplastic and immunomodulating agents
MMusculo-skeletal system
NNervous system
PAntiparasitic products, insecticides, and repellents
RRespiratory system
SSensory organs
VVarious

Second Level

The second level of the code indicates the therapeutic subgroup and consists of two digits.

  • Example: C03 Diuretics.

Third Level

The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.

  • Example: C03C High-ceiling diuretics.

Fourth Level

The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.

  • Example: C03CA Sulfonamides.

Fifth Level

The fifth level of the code indicates the chemical substance and consists of two digits.

  • Example: C03CA01 furosemide.

Other ATC Classification Systems

ATCvet

The Anatomical Therapeutic Chemical Classification System for veterinary medicinal products (ATCvet) is used to classify veterinary drugs. ATCvet codes can be created by placing the letter Q in front of the ATC code of most human medications.

  • For example, furosemide for veterinary use has the code QC03CA01.

Some codes are used exclusively for veterinary drugs, such as QI Immunologicals, QJ51 Antibacterials for intramammary use or QN05AX90 amperozide.

Herbal ATC (HATC)

The Herbal ATC system (HATC) is an ATC classification of herbal substances; it differs from the regular ATC system by using 4 digits instead of 2 at the 5th level group.

The herbal classification is not adopted by WHO. The Uppsala Monitoring Centre is responsible for the Herbal ATC classification, and it is part of the WHODrug Global portfolio available by subscription.

Defined Daily Dose

The ATC system also includes defined daily doses (DDDs) for many drugs. This is a measurement of drug consumption based on the usual daily dose for a given drug. According to the definition, “[t]he DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.”

Adaptations and Updates

National issues of the ATC classification, such as the German Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen, may include additional codes and DDDs not present in the WHO version.

ATC follows guidelines in creating new codes for newly approved drugs. An application is submitted to WHO for ATC classification and DDD assignment. A preliminary or temporary code is assigned and published on the website and in the WHO Drug Information for comment or objection. New ATC/DDD codes are discussed at the semi-annual Working Group meeting. If accepted it becomes a final decision and published semi-annually on the website and WHO Drug Information and implemented in the annual print/on-line ACT/DDD Index on 01 January.

Changes to existing ATC/DDD follow a similar process to become temporary codes and if accepted become a final decision as ATC/DDD alterations. ATC and DDD alterations are only valid and implemented in the coming annual updates; the original codes must continue until the end of the year.

An updated version of the complete on-line/print ATC index with DDDs is published annually on 01 January.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System >; 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.