Pharmacokinetic and pharmacodynamic profile of icatibant

• Published in: Clinical pharmacology and therapeutics 2004-02, Vol.75 (2), p.P56-P56
• Main Authors: Perrin, Y., Nguyen, M. T., Rousso, P., Buclin, T., Rochat, B., Decosterd, L., Appenzeller, M., Jaquet, F., Brunner‐Ferber, F., Rosenkranz, B., Knolle, J., Biollaz, J.
• Format: Article
• Language: English
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2003.11.212

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