Pharmacokinetics of multiple dosing
• Multiple dosing is used to attain and maintain drug concentrations within a certain range over an extended period of time
- Maintain the drug’s therapeutic effect
- Minimize the likelihood of adverse (toxic) effects
• Important for the treatment of chronic diseases
ACCUMULATION
• When a drug product is given repeatedly (e.g., every 12 hours) over time with a fixed dosing interval (time between doses), it will accumulate if some drug remains in the body from previous doses
Superposition Principle
Drug accumulates if subsequent dose is given before previous dose is completely eliminated
3 Points on ACC/SS: Inference
- Drug accumulates if given more frequently than every 4-5 half lives
- On repeated dosing, steady state will be reached
- Dose administered = Amount lost from body
(rate in = rate out) - The extent of accumulation depends upon the frequency of administration and half-life
- More frequently drug is given in relationship to its t1/2, greater will be the accumulation
Steady State
- The maximum and minimum amounts of drug in the body during a dosing interval approach upper limits
• Eventually, the amount lost in each interval equals the amount gained, which is the dose - For this reason, drug in the body is then said to be at steady state or at plateau
Time to Reach Steady State
- The approach to steady state (i.e., the time to reach steady state) is dependent on the half-life of the drug and independent of the dosing frequency
- If the same dose is given twice as frequently, the average amount in the body doubles and the relative fluctuation is less, but the time to reach steady state at the higher levels is the same
Accumulation of a drug is related to…
• the dosing interval and elimination rate of drug
– When the dosing interval is long relative to the time needed to eliminate the drug, accumulation is low.
– When the dosing interval is short relative to the time needed to eliminate the drug, accumulation is high.
Accumulation Index (dependent/independent)
- More frequently drug is given in relationship to its t1/2, greater will be the accumulation
- Accumulation index is dependent on t1/2 and t, independent of dose
- Max amount (single dose) x accumulation index = Max amount multiple dose
Accumulation, Multiple Extravascular Doses
- Extensive accumulation is common to drugs with long elimination half-lives
- Absorption is usually relatively fast as compared with elimination (especially for oral administration)
- The equations for intravenous doses generally apply to oral and other extravascular routes as well
- However, not all of the administered dose may be bioavailable
- Thus, all of the relationships in Table 9-2 need to incorporate F as shown in Table 9-3
Fluctuation at steady state can be predicted by…
adding the concentration-time profiles within each successive dosing interval as subsequently shown
