Which statement correctly distinguishes linear from nonlinear pharmacokinetics?

• A. Linear PK: exposure is proportional to dose with constant CL; Nonlinear PK: exposure not proportional due to saturable processes
• B. Linear PK: exposure is inversely proportional to dose
• C. Linear PK: CL changes with dose; Nonlinear PK: CL constant
• D. Linear PK: Vd changes with dose; Nonlinear PK: Vd constant

Answer: (A)

Linear pharmacokinetics means that as the dose increases, exposure (AUC and Cmax) increases in direct proportion because clearance remains constant across the dose range. In this situation, the elimination half-life stays the same if volume of distribution stays unchanged. Nonlinear pharmacokinetics happens when a process governing clearance or distribution becomes saturated at higher concentrations, so clearance becomes dose-dependent and exposure no longer scales proportionally with dose. A classic example is saturable metabolism: once enzymes are saturated, clearance falls as dose rises, causing AUC to rise more than proportionally. This distinction—dose-proportional exposure with constant clearance for linear PK versus non-proportional exposure due to saturable processes for nonlinear PK—is why the correct statement emphasizes proportional exposure with constant clearance for linear PK and non-proportional exposure for nonlinear PK. The other options misstate the relationships (inverse proportionality, dose-dependent clearance in linear PK, or dose-dependent changes in volume) and don’t reflect the defining difference.