Drug Half-Life and Dosing
How elimination half-life determines dosing frequency, time to steady state, and drug accumulation during chronic therapy.
What Is Half-Life?
The elimination half-life (t1/2) is the time required for the plasma concentration of a drug to decrease by 50%. It is determined by two fundamental parameters:
t1/2 = (0.693 x Vd) / CL
Where Vd is volume of distribution and CL is clearance. A drug with a large Vd or low clearance will have a long half-life.
Half-Life and Dosing Frequency
The goal of repeated dosing is to maintain plasma concentrations within the therapeutic window — above the minimum effective concentration (MEC) and below the toxic concentration. General guidelines:
- Short half-life drugs (< 4 hours): require frequent dosing or sustained-release formulations. Example: immediate-release morphine (t1/2 ~2-3 hours) dosed every 4 hours.
- Moderate half-life drugs (4-12 hours): typically dosed 2-3 times daily. Example: metoprolol (t1/2 ~3-7 hours).
- Long half-life drugs (> 24 hours): once-daily or less frequent dosing. Example: amlodipine (t1/2 ~35 hours) dosed once daily.
Time to Steady State
During repeated dosing at regular intervals, drug accumulates until the rate of administration equals the rate of elimination. This equilibrium is called steady state and is reached after approximately 5 half-lives, regardless of dose or dosing interval.
| Half-Lives Elapsed | % of Steady State |
|---|---|
| 1 | 50% |
| 2 | 75% |
| 3 | 87.5% |
| 4 | 93.75% |
| 5 | 96.875% |
A drug with a 12-hour half-life reaches steady state in about 2.5 days. Amiodarone (t1/2 ~40-55 days) takes 6-9 months without a loading dose.
Loading Doses
When immediate therapeutic levels are needed and the half-life is long, a loading dose rapidly achieves target concentrations:
Loading dose = Vd x Cp(target) / F
Examples include digoxin (t1/2 ~36 hours), phenytoin (t1/2 ~22 hours), and amiodarone. The maintenance dose then sustains the concentration.
Accumulation Factor
During chronic dosing, the accumulation factor predicts how much higher steady-state concentrations will be compared to the first dose:
Accumulation factor = 1 / (1 - e^(-0.693 x tau/t1/2))
Where tau is the dosing interval. Drugs dosed at intervals shorter than their half-life accumulate more.
Key Takeaways
- Half-life depends on both volume of distribution and clearance
- Dosing interval is guided by half-life to maintain therapeutic concentrations
- Steady state is reached after approximately 5 half-lives
- Loading doses are used when the half-life is too long to wait for steady state
- Drug accumulates more when the dosing interval is shorter than the half-life