What it means
After dosing, a drug's plasma concentration rises, peaks at Cmax (at time tmax), then declines as the drug is distributed and eliminated. The area under the concentration-time curve (AUC) is the integral of this profile — geometrically, the area of the region bounded by the curve and the time axis. It integrates concentration over every moment of time, so it captures not just the peak but the full duration and extent of drug exposure.
AUC is directly proportional to the total amount of drug that entered the systemic circulation (dose × F) and inversely proportional to systemic clearance: AUC = Dose × F / CL. For linear kinetics, doubling the dose doubles the AUC — this property (dose proportionality) is tested in Phase I trials. For nonlinear kinetics (e.g. phenytoin, alcohol), AUC increases disproportionately with dose.
AUC is the cornerstone metric in three major applications: (1) bioequivalence testing — regulatory agencies require AUC0-t and AUC0-∞ ratios within 80–125% for generic drug approval; (2) exposure-response modelling — AUC/MIC drives antibacterial killing for concentration-independent antibiotics; (3) dose individualisation — carboplatin dosing uses the Calvert formula targeting AUC 5–7 mg/mL·min. The FDA bioequivalence guidance ↗ and EMA guideline on bioequivalence ↗ specify AUC requirements in detail.
Formula
| Equation | Variables | Notes |
|---|---|---|
| AUC0-∞ = AUC0-t + Clast / ke | Clast = last measurable concentration; ke = elimination rate constant | Single-dose AUC by NCA |
| AUC = Dose × F / CL | F = bioavailability; CL = systemic clearance | From pharmacokinetic relationships |
| Trapezoid = (C1+C2)/2 × Δt | C1, C2 = adjacent concentrations; Δt = time interval | Linear trapezoidal rule (ascending phase) |
| Trapezoid = (C1−C2)/ln(C1/C2) × Δt | For descending concentrations only | Log trapezoidal rule (elimination phase) |
| Css,avg = AUC_tau / τ | τ = dosing interval; AUC_tau = area over one interval at steady state | Average steady-state concentration |
The linear-log trapezoidal method (linear up to Cmax, log thereafter) is the FDA-recommended approach for AUC calculation in bioequivalence studies. Uniform sampling times across treatments are required for accurate comparison. See Gabrielsson & Weiner non-compartmental analysis ↗.
Example: ibuprofen AUC calculation
Using a simplified 6-point concentration profile for ibuprofen ↗ (t½ ≈ 2 h, Cmax ≈ 30 µg/mL at t = 1 h):
| Time (h) | Conc. (µg/mL) | Trapezoid area | Cumulative AUC |
|---|---|---|---|
| 0 | 0 | — | 0 |
| 1 | 30.0 | 15.0 | 15.0 |
| 3 | 7.5 | ~33.7 (log-trap) | ~48.7 |
| 5 | 1.9 | ~8.5 (log-trap) | ~57.2 |
| 7 | 0.47 | ~2.1 (log-trap) | ~59.3 |
| ∞ | — | +0.47/ke = +1.4 | ~60.7 µg·h/mL |
For comparison, the theoretical AUC0-∞ from PK parameters: AUC = F × Dose / CL. With 400 mg ibuprofen (F ≈ 0.80, CL ≈ 5.3 L/h): AUC ≈ 400 × 0.80 / 5.3 ≈ 60 mg·h/L — consistent with the trapezoidal estimate above. See the ibuprofen DailyMed label ↗ for published PK data.
Common mix-ups
AUC reflects total exposure (efficacy/toxicity driven by sustained concentration), while Cmax reflects peak exposure (relevant for concentration-dependent effects and toxicity). Both are required for bioequivalence. A slow-release formulation may have the same AUC but much lower Cmax than an immediate-release product.
AUC0-t (measured) is always smaller than AUC0-∞ (extrapolated). The FDA requires the terminal extrapolation to contribute ≤20% of AUC0-∞ in bioequivalence studies. If it exceeds 20%, the sampling schedule was too short and the AUC0-∞ estimate is unreliable.
Dose proportionality (AUC doubling with dose doubling) holds only for linear, first-order kinetics. Drugs with nonlinear kinetics (phenytoin, ethanol, high-dose aspirin) show disproportionate AUC increases. This is tested using dose-normalised AUC comparisons.
Plasma AUC measures systemic exposure but not necessarily drug concentration at the site of action. For CNS drugs, the relevant AUC is brain tissue concentration. PK/PD modelling using effect-compartment or PBPK approaches links plasma AUC to pharmacodynamic outcome.
FAQ
What does AUC mean in pharmacokinetics?
AUC (area under the concentration-time curve) is the integral of plasma drug concentration over time. It represents total drug exposure — the total amount of drug that reached the systemic circulation over the measurement period. AUC is expressed in units of concentration × time (e.g. mg·h/L or µg·h/mL). See the StatPearls pharmacokinetics overview ↗ for context.
What is the difference between AUC0-t and AUC0-∞?
AUC0-t (or AUClast) is calculated from time zero to the last measurable concentration — directly from data. AUC0-∞ (or AUCinf) extrapolates to infinite time: AUC0-∞ = AUC0-t + Clast / ke. For bioequivalence studies, the FDA guidance ↗ requires both AUC0-t and AUC0-∞.
How is AUC calculated from PK data?
AUC is calculated using the linear-log trapezoidal rule: linear rule for ascending concentrations (up to Cmax), log rule for the descending phase. Each trapezoid: area = (C1 + C2)/2 × (t2−t1). The terminal area is added as Clast / ke. Software like Phoenix WinNonlin ↗ and open-source PKNCA automate NCA calculations ↗.
How is AUC related to clearance?
Systemic clearance (CL) = DoseIV / AUCIV. After oral dosing, apparent oral clearance CL/F = Doseoral / AUCoral. AUC is inversely proportional to clearance — reducing CL (e.g. by a CYP inhibitor) proportionally increases AUC, risking toxicity for narrow-TI drugs.
What is AUC used for in bioequivalence studies?
In bioequivalence studies, AUC0-t, AUC0-∞, and Cmax are the primary PK endpoints. Two formulations are bioequivalent if the 90% CI for test/reference AUC and Cmax ratios fall within 80–125%. See the FDA bioequivalence guidance ↗ and EMA BE guideline ↗.
Does AUC reflect drug efficacy or toxicity?
For many drugs, AUC correlates with both efficacy and toxicity. In PK/PD modelling, AUC/MIC is a key exposure-response metric for time-independent antibiotics (fluoroquinolones, aminoglycosides). For anticancer drugs (e.g. carboplatin), AUC is used directly in the Calvert formula ↗ for dose calculation. The therapeutic index determines the acceptable AUC range.
What is AUC_tau in repeated dosing?
AUC_tau is the area under the concentration-time curve over one dosing interval (τ) at steady state. For linear kinetics, AUC_tau = AUC0-∞ (single dose). Average steady-state concentration: Css,avg = AUC_tau / τ. For nonlinear kinetics (e.g. phenytoin), AUC_tau may exceed single-dose AUC0-∞ due to saturable clearance.