Concept: Dose Intensity

Introduction

Dose intensity, measured using Defined Daily Dose (DDD) and Prescribed Daily Dose (PDD), can be used in several ways, the primary one being to describe the population's use of pharmaceuticals. The PDD is a measure of the average daily amount of a drug that is actually prescribed while the DDD is a measure of assumed average maintenance dose per day for a drug used as a main indication for adults. The DDD is used as a measure of "therapeutic intensity" while the PDD is most often used in studies of particular drugs and in pharmacoepidemiologic studies that examine dose/response issues.

Intensity indicators describe types and numbers of prescription drugs used by the population:


• Number of Prescriptions Dispensed - Caution: quantity of prescription items varies from prescription to prescription.
  
• Number of Different Drugs Dispensed - normally expressed as the average number of different drugs, defined at 4th level ATC, dispensed per year per user/resident.
  
• Number of DDDs - assumed average maintenance dose per day for drug which is mainly indicated for adults.

Example - DDD and PDD: Manitobans were found to have been dispensed 27.3 DDDs of antibiotics (ATC 'J01')/1000 residents/day in 1997/1998, equivalent to a point prevalence (one fiscal year) of antibiotic use in the population. We would know from this number that if all users of antibiotics took exactly 1 DDD of antibiotic/day, then Manitoba was treating 27.3 persons out of every 1000 persons, resident in Manitoba, every day of the year. If the actual daily intake of a drug class in the population deviates substantially from the DDD, then this measure of "therapeutic intensity" is a poor one for point prevalence. In this case, it is advisable to consider the prescribed daily dose (PDD) of each of the most frequently dispensed antibiotics to see how much deviation there is from the DDD. The major limitation to the use of PDD is that data on different drugs cannot be collapsed.


1. Defined Daily Dose (DDD)
   • Calculating DDD Rates
     
   • Using DDDs Clinically
2. Prescribed Daily Dose (PDD)
3. SAS Code

1. Defined Daily Dose (DDD)

The DDD for a drug is its assumed average maintenance dose per day for a drug used as a main indication in adults. The rate of the number of DDDs dispensed to the population (of residents or users) per day and per year can be calculated to measure various aspects of intensity. This does not necessarily reflect the actual amount or dose used. The DDD represents a measure of "therapeutic intensity" that allows data to be collapsed on drugs as diverse in action and potency as amoxicillin and erythromyin:


• Penicillins (extended spectrum J01CA04): 1 DDD of Amoxicillin = 1.0g/day
  
• Macrolides (J01FA01): 1 DDD of Erthromycin = 0.5g/day



Total DDDs (e.g., amoxicillin 250 mg) =

Dosage form strength (250mg) X Quantity of amoxicillin 250 mg dispensed ___________________________________________________________ WHO assigned DDD for amoxicillin (1 g or 1000 mg)

DDDs are assigned per ATC 5th level by the WHO Collaborating Centre for Drug Statistics Methodology. See the WHO Collaborating Centre for Drug Statistics Methodology Web Site at: http://www.whocc.no/ddd/definition_and_general_considera/ for more information on DDDs.

For some types of drugs, DDDs have not been assigned by WHO either because it is difficult to find appropriate DDDs (e.g. dermatologicals or drugs combined in the same dosage form) or because no requests for DDD have been made to the WHO Centre.

Calculating DDD Rates

Four different types of rates can be obtained for the number of DDDs: per day, per year, per resident, or per user. Rates can also be age- and sex- adjusted using either the Manitoba population or the group of user proportions for the year of analysis and a direct method of standardization.


• The numerator, which can be summed for an entire year of usage, yielding the number of DDDs dispensed in the population, is:
  
  quantity / (DDD/strength) = # of DDDs, where
  
  
  • quantity = the quantity dispensed
    
  • DDD = the level assigned by the WHO
    
  • strength = the strength of the drugs in the same unit as the DDD.
  
  
• The denominator is the number of residents or users respectively.

Example: ( (Metge et al. (1999) )

Consider the DDD rate calculation for 600 mg tablets of potassium chloride. The DDD for potassium chloride is 3.0 g per day, so the denominator in the above formula is 3.0 g/600 mg = 5. That is, 5 tablets are required to make up 1 DDD. For example, if 3,000,000 tablets were dispensed to the population in a year, then the # of DDDs would be 3,000,000 tablets/5 tablets per DDD = 600,000 DDDs per year.

(Note: Analyses for this study were limited to solid dosage forms (tablets and capsules) due to inconsistency in how quantities are measured; (e.g.: a 200 mL bottle of 250 mg/5 mL amoxicillin liquid could be described as: 1 (bottle), 200 mL, 100 g or even 10,000 mg.). This example also has been somewhat simplified, since rates were age- and sex- adjusted, which required calculating the DDDs at the claim level).


1. Rates per residents per year (assuming a population of 1 million residents)

   # of DDDs per year per 1000 residents for potassium chloride
   = 600,000 DDDs per year / 1,000,000 residents * 1000
   = 600 DDDs per 1000 residents per year
   
   This could be interpreted as an estimate of how many days of treatment every resident, if placed on the drug, would have consumed in a year.

2. Rates per residents per day

   # of DDDs per day per 1000 residents
   = 600,000 DDDs per year / 365 days per year / 1,000,000 residents * 1000
   = 1.6 DDDs per 1000 residents per day
   
   This provides a rough estimate of the proportion of the population treated daily with a specific drug.

3. Rates per user per year (assuming actual number of users of potassium chloride of 10,000)

   # of DDDs per year per user
   = 600,000 DDDs per year / 10,000 users
   = 60 DDDs per user per year
   
   This is interpreted as the average duration of treatment (number of days per year) for every user of the drug/drug class.

4. Rates per user per day - to determine whether the DDD is close to the average daily maintenance dose for the drug's main indication (as determined by WHO).

   # of DDDs per day per user
   = 600,000 DDDs per year / 365 days per year / 10,000 users
   = 0.16 DDDs per user per day
   
   We expect this measure to be close to 1 for drugs used for chronic diseases (i.e., for drugs for which the DDD is likely to be prescribed for every user for every day of the year). To the extent that users are not dispensed 1 DDD per day of a group of drugs depends on the objective of the research.

Using DDDs Clinically

A clinical measure can also be calculated to help interpret the DDDs/user/day value which assumes dispensation to users over an entire year. (Note that age- and sex- adjustment, if needed, are done prior to the calculation).

This can be done in two steps:

1) Calculate an intermediate rate of the number of days supplied per user by summing the number of days supplied (DAYSUPP) recorded on each prescription claim (over a year), and dividing by the number of users. For example, if the sum of the number of days supplied of potassium chloride for the year was 1,210,000 days (assuming 10000 users again), then the average number of days supplied per user would be:

1,210,000 days / 10,000 users
= 121 days supplied per user (per year)

2) Calculate a clinical measure of how the drug (potassium chloride in this case) is actually being used by dividing the rate of the # of DDDs per user by the rate of the number of days supply per user:

# of DDDs per user per year / avg. days supplied per user
= 60 DDDs per user per year / 121 days supplied per user per year
= 0.49 DDDs / day supplied

DDDs used this way should equal 1 if the drug being examined is primarily used for its main indication at its recommended dose. Values greater than 1 or less than 1 could indicate that the drug is being used primarily for a different indication at a different dose, or that the drug is being over or under-dosed for its main indication.

If age and sex adjustment are not needed:

# of DDDs per year / # of days supplied per year
= 600,000 DDDs per year / 1,210,000 days supplied per year
= 0.49 DDDs per day supplied

This method avoids the rates altogether, and the DDDs can still be collapsed across different drugs. For example, the different groups of drugs used to treat hypertension could be described using this clinical measure and interpretation of DDD.

2. Prescribed Daily Dose (PDD)

Prescribed Daily Dose (PDD) is the average daily amount of a drug that is actually prescribed; it can be calculated as the ratio of two rates, which can be age- and sex- adjusted using either the Manitoba population or the group of user proportions for the year of analysis and using a direct method of standardization. PDD is calculated per person for solid dosage forms only (tablets and capsules). This is due to inconsistency in how quantities are measured; for example, a 200 mL bottle of 250 mg/5 mL amoxicillin liquid could be described as: 1 (bottle), 200 mL, 100 g or even 10,000 mg).

1) Rate 1: (quantity of the drug dispensed * strength of the drug) summed over the year/ # of users


Example: PDD rate calculation for 600 mg tablets of potassium chloride.

Numerator (in grams) - assuming 3,000,000 tablets dispensed to the population in a year:

3,000,000 tablets * 0.6 g per tablet
= 1,800,000 g

Denominator - assuming 10,000 users:

1,800,000 g per year / 10,000 users
= 180 g per user per year

2) Rate 2: (average number of days supplied per user): number of days supplied (DAYSUPP) summed for all claims/number of users .

Example: assuming 1,210,000 days supplied of potassium chloride for the year:

1,210,000 days / 10,000 users
= 121 days supplied per user, on average, (per year)

3) Ratio: Clinical measure of PDD - divide the first rate by the second rate

Example: 180 g per user per year / 121 days supplied per user per year

= PDD of 1.49 g per user per day

A comparison of a drug's PDD with its DDD gives one an insight into actual use of the drug when compared to its most common and recommended use. The DDD for potassium chloride, for example, is 3 g.

If age and sex adjustment are not needed:

total quantity * strength / total days supplied
= 3,000,000 tablets * 0.6 g per tablet / 1,210,000 days supplied
= 1.49 g per day supplied per user

Note:

The exposure to treatment can vary depending on which drugs are being studied. For example, in studies of the effect of exposure to corticosteroids on fracture in persons with inflammatory bowel disease (IBD) or exposure to 5-aminosalicylic acid (5-ASA) as a precursor to colorectal cancer in persons with IBD, exposure for corticosteroids had only to be 28 days; for 5-ASA treatment the exposure requirement was 90 days for oral medications and 120 days for rectal medications.