STEADY-STATE PHARMACOKINETICS AND BIOAVAILABILITY OF TOTAL AND UNBOUND DISOPYRAMIDE IN CHILDREN WITH CARDIAC-ARRHYTHMIAS

We studied the pharmacokinetics of the total (protein-bound plus-unbound) and unbound forms of disopyramide (DP) at steady-state in six children (aged 5.2 to 12.2 years) with cardiac arrhythmias who had received repeated oral DP therapy. Maximum concentrations after the oral dose were reached at 2.5 +/- 1.1 h (mean +/- SD) for both total and unbound DP. The bioavailabilities calculated from total and unbound plasma concentration-time curves were 99 +/- 23 and 89 +/- 27% of the dose, respectively. These parameters seen in our children are similar to those reported from adult subjects. The mean elimination half-lives (t1/2), volumes of distribution, and total body clearances (CL) of total and unbound DP were 3.15 +/- 0.64 and 2.50 +/- 0.37 h, 1.02 +/- 0.25 and 2.60 +/- 0.38 L/kg, and 3.79 +/- 0.82 and 13.12 +/- 2.60 ml/min/kg, respectively. These mean CL and t1/2 values are considerably greater and shorter, respectively, than those reported from adult subjects. The findings indicate that the greater doses of DP per kg of body weight reportedly required for attaining a therapeutic plasma drug level in pediatric age patients should be due to a greater drug CL in children than in adults. A sustained-release preparation of DP may be required for pediatric patients to minimize a large fluctuation of plasma drug levels during the dosing intervals.