Pharmacokinetic and pharmacodynamic profile of icatibant

Icatibant, a potent bradykinin (BK) antagonist specific for B2 receptors, was administered i.v. to 18 healthy males to assess its safety, pharmacokinetic, and pharmacodynamic profile for onset and duration of action. Part I (3 panels of 4 subjects) compared single 1h and 4h infusions (0.005 to 3.2 mg/kg) in ascending, double‐blind, placebo‐controlled design. Part II tested a 24h (0.15 mg/kg/day) vs. repeated 1h infusions (0.5 mg/kg q8h) in double‐blind cross‐over design. Icatibant (with 2 major metabolites) concentration was assessed by LC‐MS‐MS, and response by repeated i.v. bolus challenges of a BK dose selected for eliciting a 10–15 mmHg blood pressure drop with reflex tachycardia (Finapress photoplethys‐mography) and facial flush (laser‐Doppler blood flowmetry). BK blockade was obtained at all doses, with dose‐dependent intensity and duration ( Fig 1), correlating with plasma concentration and lacking hysteresis. BK dose increase (4‐fold) overcame blockade, suggesting competitive inhibition. Icatib‐ant has a rapid distribution and elimination (half‐life 1.8h) and linear kinetics over the dose range tested. It was well tolerated up to 1.6 mg/kg but 3.2 mg/kg induced transient head/trunk flushing, itching, with one orthostatic hypo‐tension. In conclusion, the ability of Icatibant to safely and sustainedly block BK effects over a wide dose range suggests an appealing therapeutic potential in conditions involving BK overproduction. Clinical Pharmacology & Therapeutics (2004) 75 , P56–P56; doi: 10.1016/j.clpt.2003.11.212