What is the definition of steady state of a drug?

Definition of Steady State of a Drug

Steady state is the pharmacokinetic condition reached when the rate of drug input equals the rate of drug elimination, resulting in stable plasma concentrations that remain constant over time during repeated dosing or continuous infusion. 1

Core Pharmacokinetic Concept

Steady state is achieved after approximately five elimination half-lives of the drug, corresponding to 24-48 hours for most beta-lactam antibiotics, though this timing varies based on the specific drug's half-life 1. At this point, the amount of drug administered during each dosing interval equals the amount eliminated, creating equilibrium 1.

• The mathematical basis relies on first-order kinetics, where drug elimination is proportional to total body content at any given time 2
• For continuous infusions, steady-state concentrations (Css) represent the plateau concentration maintained throughout the infusion 1
• For intermittent dosing, steady state refers to when the peak and trough concentrations become consistent between dosing intervals 1

Time Course to Steady State

The time required to reach steady state depends primarily on the elimination half-life, not the dose or dosing interval 1. After five half-lives, approximately 97% of steady state is achieved 1.

• For drugs with short half-lives (e.g., most beta-lactams), steady state occurs within 24-48 hours 1
• For drugs with long half-lives (e.g., digoxin with normal renal function: 1.5-2 days), steady state takes 1-3 weeks 2
• In anuric patients, digoxin's half-life extends to 3.5-5 days, requiring 2.5-3.5 weeks to reach steady state 2

Loading Doses and Accelerated Steady State

A loading dose can achieve therapeutic concentrations immediately, bypassing the gradual accumulation period 2. This approach is particularly useful when rapid therapeutic effect is needed.

• Loading doses should equal the desired steady-state body stores of the drug 2
• After a loading dose, maintenance dosing maintains steady state rather than building toward it 2
• The maintenance dose equals the peak body stores multiplied by the percentage of daily loss through elimination 2

Clinical Measurement and Monitoring

Blood sampling for therapeutic drug monitoring should occur after steady state is reached to ensure accurate interpretation 1. Sampling before steady state yields concentrations that do not reflect the eventual therapeutic or toxic potential.

• For intermittent administration, measure trough concentrations (just before the next dose) 1
• For continuous infusions, measure steady-state concentrations at any time during the infusion 1
• Sampling should be performed 24-48 hours after treatment initiation or any dosage change 1
• For digoxin, allow 6-8 hours post-dose for tissue distribution equilibrium before sampling, as early high serum concentrations do not reflect concentrations at the site of action 2

Factors Affecting Time to Steady State

Any change in elimination kinetics alters both the time to reach steady state and the eventual steady-state concentration 1.

• Renal impairment prolongs elimination half-life, extending time to steady state and increasing eventual steady-state concentrations 1, 2
• Hepatic dysfunction may alter metabolism and elimination, though digoxin metabolism is not dependent on cytochrome P-450 2
• Significant changes in circulatory, renal, or hepatic function require repeat therapeutic drug monitoring 1
• Fluid resuscitation, albumin administration, and renal replacement therapy can dramatically alter pharmacokinetics in critically ill patients 1

Steady State in Special Populations

Critically ill patients exhibit unpredictable pharmacokinetic variability that makes steady-state predictions unreliable without therapeutic drug monitoring 1.

• Severe sepsis, septic shock, and burns cause major pathophysiological changes affecting drug distribution and elimination 1
• Hydrophilic antibiotics (aminoglycosides, vancomycin, beta-lactams) show particularly high between- and within-individual variability 1
• Children demonstrate additional age-related differences in volume of distribution, metabolism, and elimination 1
• Morbid obesity, acute kidney injury, and continuous renal replacement therapy further complicate predictions 1

Steady-State Concentration Relationships

At steady state, plasma concentrations equilibrate with tissue concentrations and correlate with pharmacologic effects 2. This equilibrium is essential for interpreting drug levels clinically.

• The steady-state volume of distribution (Vss) represents the ratio of total drug in the body to plasma concentration at steady state 3, 4
• For vancomycin, target residual concentrations of approximately 20 mg/L correlate with therapeutic AUC24h/MIC ratios 1
• For beta-lactams, maintaining concentrations above 4-6 times the MIC throughout the dosing interval optimizes bactericidal activity 1

Common Pitfalls

Measuring drug concentrations before steady state is reached leads to misinterpretation and inappropriate dose adjustments 1.

• Serum concentrations continue rising until steady state, so early measurements underestimate eventual exposure 5
• The initial concentration at the time of dose change affects how quickly a new steady state is approached, not just the half-life 5
• For drugs with active metabolites, the metabolite's half-life must also be considered 1
• Digoxin concentrations sampled at 24 hours versus 8 hours post-dose differ by 10-25% depending on renal function, even at steady state 2