Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution and effect of food.
Pleconaril is an orally active broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (200 mg) of pleconaril oral solution in fed and fasting humans. Twelve healthy adult subjects (18.7 to 39 years of age) participated in this study. Each subject received a single 200-mg dose of pleconaril oral solution, both coadministered with a standard English breakfast and following a 10-h predose fast. There was a minimum 7-day washout period between pleconaril doses. Repeated blood samples (n = 10) were obtained over 24 h postdose, and the pleconaril level in plasma was quantified by gas chromatography. Plasma concentration-versus-time data were curve fitted for each subject by using a nonlinear weighted least-squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. Pleconaril disposition was best characterized by a one-compartment open model with first-order absorption. The apparent bioavailability of pleconaril oral solution was significantly increased with the administration of food. The area under the concentration-time curve and maximum concentration of pleconaril in plasma achieved following the standard English breakfast (i.e., 9.08 +/- 3.23 mg/liter . h and 1.14 +/- 0.58 mg/liter, respectively) were 2.2- and 2.5-fold higher, respectively than those achieved in the fasting state (i.e., 4.08 +/- 2.74 mg/liter . h and 0.46 +/- 0.30 mg/liter, respectively). Mean plasma pleconaril concentrations 12 h after a single 200-mg oral dose (fed, 0.25 +/- 0.2 mg/liter; fasting, 0.11 +/- 0.10 mg/liter) in healthy adults remained greater than that required to inhibit more than 90% of the enteroviruses in cell culture (i.e., 0.07 mg/liter). To enhance the oral bioavailability of pleconaril, coadministration with a fat-containing meal is recommended.
Section of Pediatric Clinical Pharmacology and Experimental Therapeutics, The Children's Mercy Hospital, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
S M
SM
Abdel-Rahman
G L
GL
Kearns
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005502:Food; D006801:Humans; D010069:Oxadiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010080:Oxazoles; D010849:Picornaviridae / Q000187:drug effects*; D012996:Solutions
D000998:Antiviral Agents; D010069:Oxadiazoles; D010080:Oxazoles; D012996:Solutions; C115201:pleconaril