Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution in children and adolescents

Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril , we conducted a single-dose, open-label study to characterize the pharmaco kinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 +/- 3.1 years) received a single 5-mg/kg of body weight oral dose of plecon aril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and plec onaril was quantified from plasma by gas chromatography. Plasma drug concen tration-time data for each subject were fitted to the curve by using a nonl inear, weighted (weight = 1/Y-calc) least-squares algorithm, and model-depe ndent pharmacokinetic parameters were determined from the polyexponential p arameter estimates. Preconaril was well tolerated hy all subjects. A one-co mpartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h pos tdose period. Pleconaril pharmacokinetic parameters (means +/- standard dev iations) for these 13 patients were as follows. The maximum concentration o f the drug in serum (C-max) was 1,272.5 +/- 622.1 ng/ml. The time to C-max was 4.1 +/- 1.5 h, and the lag time was 0.75 +/- 0.56 h. The apparent absor ption rate constant was 0.75 +/- 0.48 1/h, and the elimination rate constan t was 0.16 +/- 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 +/- 3,411.82 ng.h/ml. The apparent total plasma clear ance was 0.81 +/- 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 +/- 2.02 liters/kg. The mean elimination half-life o f pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 1 2 h (250.4 +/- 148.2 ng/ml) and 24 h (137.9 +/- 92.2 ng/ml) after the singl e 5-mg/kg oral dose in children were higher than that: from in vitro studie s reported to inhibit >90% of nonpolio enterovirus serotypes (i.e., 70 ng/m l). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dos e of pleconaril for therapeutic trials in pediatric patients with enterovir al infections.