Pharmacokinetics and pharmacodynamics of intravenous cibenzoline in normal volunteers.

The pharmacokinetics of intravenous (IV) cibenzoline were studied in six healthy male volunteers ranging in age from 51 to 78 years. The subjects received intravenous (IV) cibenzoline 100 mg over 20 minutes, and plasma and urine specimens were collected for 48 hours. Cibenzoline plasma concentrations at the end of the infusion ranged from 730 to 1,420 ng/mL and exhibited triexponential decline thereafter. The following mean model independent pharmacokinetic parameters were calculated from the plasma and urine concentration data: terminal half-life, 9.8 hours (range, 8.5-11.9); plasma clearance, 523 mL/min (range, 387-687); volume of distribution, 445 L (range, 328-506); and renal clearance, 289 mL/min (range, 202-334). Approximately 31% to 59% of the dose was recovered unchanged in the urine in 48 hours. A triexponential pharmacokinetic equation with zero order input was used to curve fit the plasma and urine data, and the model-dependent parameters agreed well with the model-independent estimates. A hysteresis loop was observed in the relationship between cibenzoline plasma concentration and QRS prolongation, indicating an initial lag between plasma concentration and effect after IV administration. Based on these results, the following preliminary dosing regimen was proposed to rapidly achieve and maintain therapeutic plasma concentrations equal to or slightly greater than 200-400 ng/mL: 0.25 mg/kg/min IV bolus over one minute followed by 1-1.5 mg/kg/hr for one hour and 0.2-0.4 mg/kg/hr for long-term infusion.