From the Guidelines
Half-Life of Drugs with Saturable Elimination
The half-life of drugs with saturable elimination increases when plasma concentration is increased.
- This is because at higher plasma concentrations, the saturable elimination pathway becomes saturated, leading to a decrease in the rate of elimination and an increase in half-life.
- As seen with heparin, the apparent biologic half-life increases from approximately 30 min after an IV bolus of 25 units/kg, to 60 min with an IV bolus of 100 units/kg, to 150 min with a bolus of 400 units/kg 1.
- Similarly, lidocaine shows non-linear or time-dependent pharmacokinetics for infusion durations > 12 h, with the half-life increasing to 3.22 h after 24 h 1.
- In contrast, aspirin has a short half-life of approximately 20 min, but its anti-thrombotic effect is saturable at doses in the range of 75 to 100 mg, and is observed with dosing intervals of 24 to 48 h due to the permanent inactivation of platelet COX-1 1.
From the Research
Effect of Saturable Elimination on Half-Life
- When plasma concentration is increased in drugs with saturable elimination, the half-life of the drug also increases 2, 3.
- This is because saturable elimination pathways can become overwhelmed at high concentrations, leading to a decrease in the rate of elimination and an increase in half-life 2.
- As a result, small changes in dosing rate can lead to large differences in steady-state concentration, and the time to achieve a given fraction of steady-state becomes longer as the dosing rate approaches the maximum elimination rate 2.
Mechanism of Saturable Elimination
- Saturable elimination occurs when the elimination pathway is capacity-limited, meaning that it can only eliminate a certain amount of drug per unit time 3.
- This can lead to nonlinear pharmacokinetics, where the rate of elimination is not proportional to the plasma concentration of the drug 3, 4.
- Saturable binding to plasma proteins or tissues can also affect the pharmacokinetics of a drug, leading to nonlinear relationships between total and unbound drug concentrations 5, 4.
Clinical Implications
- The increase in half-life at high concentrations can lead to abnormal drug accumulation and increased risk of toxicity 3.
- Saturable elimination can also lead to drug interactions, such as mutual displacement from plasma albumin binding sites, inhibition of active drug transport and metabolism, or enzyme induction 3.
- Understanding the effects of saturable elimination on half-life is important for optimizing drug dosing regimens and minimizing the risk of adverse effects 2, 5.