doseproportionality

Dose proportionality is a pharmacokinetic property in which drug exposure increases in direct proportion to the administered dose. In a dose-proportional system, key exposure metrics such as the area under the concentration–time curve (AUC) and the maximum concentration (Cmax) rise in proportion to dose over the studied range. Dose proportionality implies linear pharmacokinetics, where clearance and other parameters remain constant with dose and the relationship between dose and exposure is scalable.

Assessment often uses multiple dose levels and statistical models. A common approach is the power model, P = a × Dose^b, where P is a PK parameter like AUC or Cmax. Taking logs gives log(P) = log(a) + b log(Dose); if b is close to 1, exposure is dose-proportional. Confidence intervals for b that include 1 support proportionality. Graphical methods, such as log-log plots of PK parameters versus dose, are also used.

Implications: Dose proportionality simplifies dosing decisions because exposure scales linearly with dose, allowing straightforward extrapolation between doses and predictable steady-state behavior. Non-proportional PK requires careful dose adjustment and may necessitate monitoring.

Causes of non-proportionality include saturable absorption, metabolism, or transport processes; time-dependent changes in clearance (e.g., autoinduction); nonlinear protein binding; and target-mediated disposition at certain concentration ranges. At the lower or higher ends of the dose range, these effects may alter proportionality.

In practice, dose proportionality is a key consideration in drug development and regulatory submission. It does not always hold over broad dose ranges, and biologics may show approximate proportionality only within a therapeutic window. Understanding proportionality informs safe and effective dosing regimens.