Steady state is a cornerstone concept in clinical pharmacokinetics. It connects dose, dosing interval, and patient-specific clearance to the drug concentrations that drive therapeutic and adverse effects. Yet, “steady state” is often misunderstood or oversimplified. This chapter explains what steady state is (and is not), how it arises under different dosing schemes, how to calculate and predict steady-state concentrations, and how to apply these ideas to individualized dosing and therapeutic drug monitoring (TDM). We highlight linear versus nonlinear behavior, infusion versus intermittent dosing, accumulation, fluctuation, loading doses, and special scenarios such as long-acting formulations, critical illness, and altered protein binding. Key takeaways Definition Steady state exists when, under time-invariant conditions, the concentration–time profile repeats identically during each dosing interval. Fundamentally, this means drug input equals drug elimination over each cycle . Mathematical Formulas (Linear Kinetics) For linear kinetics, the average steady-state concentration (Css,avg) depends only on the dose rate and clearance (CL). Oral/Intermittent Dosing: Css,avg = (F × Dose) / (τ × CL) Continuous Infusion: Css = R0 / CL Key Kinetic Principles Time to Steady State: This is determined solely by the elimination half-life (t1/2), not the dose. It takes approximately 4–5 half-lives to approach >90–97% of steady state . Accumulation and Fluctuation: These are governed by the relationship between the dosing interval (τ) and the half-life. A longer τ typically increases peak–trough variation . Nonlinear Kinetics: Factors such as saturation or autoinduction (time-varying kinetics) will shift the steady state, invalidating simple linear predictions . Clinical Application Sampling: When using concentration targets, samples should be drawn at or near steady state. Protein Binding: Consider unbound drug concentrations if protein binding is altered (e.g., hypoalbuminemia) . Defining Steady State What steady state means Steady state is achieved during multiple dosing or continuous infusion when the amount of drug entering the body per unit time equals the amount eliminated per unit time, given constant pharmacokinetic parameters (clearance, volume, bioavailability). At that point, concentrations over each dosing interval repeat in a stable pattern: same peak, trough, and area under the curve (AUC) each cycle . Important nuances: Distinguishing average, peak, and trough at steady state Mathematical Foundations Linear kinetics and superposition For most dose ranges, many drugs follow linear (first-order) kinetics: pharmacokinetic parameters are constant, and exposure (AUC) is proportional to dose. Multiple dosing and infusion can be handled using superposition: the total concentration is the sum of individual single-dose contributions shifted by integer multiples of the dosing interval . Key Linear Pharmacokinetic Relations Fundamental Equations Average Steady-State Concentration: Css,avg = (F × Dose / τ) / CL AUC over one Dosing Interval: AUCτ,ss = (F × Dose) / CL Note: This is equivalent to the single-dose AUC for IV administration (AUC = Dose/CL). Fraction of Steady State Reached (at time t): Fraction = 1 − e−k × t Where k = ln(2) / t1/2 Time to Steady State The time required to reach steady state depends only on the elimination half-life (t1/2). 1 half-life: 50% reached 2 half-lives: 75% reached 3 half-lives: ~87.5% reached 4 half-lives: ~94% reached 5 half-lives: ~97% reached General Rule: It typically takes 4 to 5 half-lives to reach clinical steady state. Accumulation Ratio (Racc) For intermittent dosing in a one-compartment model: Racc = 1 / (1 − e−k × τ) Intuition: A shorter dosing interval (τ) relative to the half-life results in a higher accumulation ratio . Fluctuation at Steady State Fluctuation is the ratio of peak to trough within a dosing interval. For one-compartment IV bolus dosing: Cmax,ss / Cmin,ss = ek × τ Thus, for a given half-life, shortening the dosing interval reduces fluctuation (more even concentrations), while lengthening it increases fluctuation . Steady State Under Different Dosing Schemes A. Continuous IV Infusion Concentration: C(t) = Css × [1 − e−k × t] (where Css = R0/CL). Stopping infusion: Leads to a mono-exponential decline: C(t) = Css × e−k × t. Clinical Strategy: Use a loading dose to reach Css rapidly. Infusions enable tight control for narrow therapeutic index drugs with short half-lives (e.g., anesthetics) . B. Intermittent IV Bolus After stabilization, the peak (post-dose) and trough (pre-dose) repeat. For a one-compartment model with immediate distribution: Peak: Cmax,ss ≈ (Dose / V) × [1 / (1 − e−k × τ)] Trough: Cmin,ss = Cmax,ss × e−k × τ Caveat: In multicompartment kinetics, "peak" sampling too early may reflect distribution phases and overestimate exposure . C. Repeated Oral Dosing Linear Validity: Css,avg formula remains valid. Absorption Rate (ka): Rapid absorption (ka >> k) yields sharper peaks/higher fluctuation. Slower absorption smooths the profile. Flip-Flop Kinetics: If ka MIC. Use short τ or continuous infusion. Concentration-Dependent (e.g., Aminoglycosides): Efficacy driven by Peak/MIC or AUC/MIC. Allow fluctuation to maximize peaks…
