Pitrakinra, a 15-kDa recombinant human interleukin-4 mutein, targets allergic Th2 inflammation by competitively binding to interleukin-4 receptor alpha to interfere with interleukin-4 and interleukin-13 action. The authors characterized pitrakinra pharmacokinetics using data from 96 atopic patients, then compared pharmacokinetics with pharmacological response in asthma following subcutaneous versus inhalation dosing. A 1-compartment systemic model with site-specific absorption describes pitrakinra pharmacokinetics following subcutaneous, nebulization, and inhalation powder delivery. Typical CL/F and V/F, referenced to subcutaneous administration, are 15.5 L/h and 67.5 L, yielding a 3.0-hour half-life of plasma decline. Absorption into the blood (half-life <or=1.0 hour, lag <or=18 minutes) is more rapid than elimination. Relative to subcutaneous injection, systemic availability of the first inhaled dose is <or=3%. Subcutaneous injection produced variable efficacy despite high systemic exposure, suggesting inadequate exposure at the site of action in some participants. Inhalation produced consistent pharmacodynamic response despite low systemic exposure. The lung appears as the primary site of pitrakinra's antiasthmatic action, supporting direct administration to the lung for the treatment of asthma.