Steady-State Pharmacokinetics
The equilibrium between drug input and elimination during chronic therapy, and how it determines average drug levels.
## What Is Steady State?
Steady state (Css) is the condition during chronic drug administration when the rate of drug input equals the rate of elimination. At steady state, plasma concentrations fluctuate around a predictable average between doses but no longer increase from one dosing cycle to the next.
## The 5-Half-Life Rule
Regardless of dose, dosing interval, or route of administration, steady state is approximately 97% complete after 5 half-lives. This is a direct mathematical consequence of first-order elimination kinetics — each half-life eliminates 50% of the difference between current and final steady-state levels.
Practical implications:
- Do not check "trough levels" for therapeutic drug monitoring before 5 half-lives of consistent dosing
- Dose adjustments take another 5 half-lives to fully reflect in new steady-state concentrations
- The same 5-half-life rule applies to drug washout after discontinuation
## Average Steady-State Concentration
For a drug given orally at regular intervals, the average steady-state concentration is:
**Css,avg = (F x Dose) / (CL x tau)**
Where F is bioavailability, CL is clearance, and tau is the dosing interval. This equation reveals that:
- Doubling the dose doubles Css,avg (for linear kinetics)
- Doubling clearance halves Css,avg
- Changing the dosing interval inversely affects Css,avg
## Peak-Trough Fluctuations
At steady state, concentrations oscillate between:
- **Css,max (peak)**: highest concentration, reached shortly after each dose. Determines peak-related side effects.
- **Css,min (trough)**: lowest concentration, measured just before the next dose. Must remain above MEC for continuous efficacy.
The magnitude of fluctuation depends on the ratio of dosing interval to half-life. Extending the dosing interval increases peak-to-trough swings. Sustained-release formulations reduce these fluctuations by slowing absorption.
## Continuous Infusion
IV infusion eliminates peak-trough oscillations entirely. The steady-state concentration during constant infusion is:
**Css = Infusion rate / CL**
This is the simplest pharmacokinetic scenario and is used for drugs with narrow therapeutic indices (e.g., aminophylline, heparin) where fluctuations are dangerous.
## When Steady State Does Not Apply
Steady-state calculations assume:
- **First-order (linear) kinetics**: drugs like phenytoin and ethanol exhibit saturable metabolism, and steady state may not behave predictably
- **Constant dosing**: missed doses or variable compliance disrupt the equilibrium
- **Stable clearance**: acute kidney injury or liver disease changes clearance mid-therapy
## Key Takeaways
- Steady state is reached after 5 half-lives of consistent dosing
- Average Css depends on dose, bioavailability, clearance, and dosing interval
- Peak-trough fluctuations increase when the dosing interval exceeds the half-life
- Continuous infusion provides the most stable plasma levels
- Non-linear kinetics, variable compliance, and changing organ function disrupt steady state