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The Effect of Oral Pleconaril on Hepatic Cytochrome P450 3A Activity in Healthy Adults Using Intravenous Midazolam as a Probe

From the Clinical Pharmacology Research Center, Research Institute (Dr Ma, Dr Nafziger, Ms Gartung, Dr Bertino), and the Department of Medicine (Dr Nafziger, Dr Bertino), Bassett Healthcare, Cooperstown, New York; and ViroPharma Incorporated, Exton, Pennsylvania (Dr Rhodes, Dr Liu).

Pleconaril is a viral capsid inhibitor under evaluation for treatment of infections caused by rhinoviruses and enteroviruses. This study evaluated the effect of pleconaril on hepatic cytochrome P450 (CYP) 3A activity as assessed by intravenous (IV) midazolam. Healthy adults received oral pleconaril 400 mg 3 times daily for 16 doses. Single-dose, IV midazolam 0.025 mg/kg was administered before and during pleconaril administration. Midazolam and pleconaril plasma concentrations were assayed by LC/MS/MS. Bioequivalence was assessed by least squares geometric mean ratios (LS-GMR) with 90% confidence intervals (90% CIs) for the measured midazolam pharmacokinetic parameters. Sixteen subjects were enrolled, and 14 subjects completed the study. Pleconaril decreased midazolam AUC_0- 28% and increased systemic clearance 39%. LS-GMR (90% CI) were 0.718 (0.674-0.765) and 1.392 (1.307-1.483), respectively. Plasma pleconaril concentrations steadily increased over time. Observed changes in midazolam AUC_0- and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.

Key Words: Pleconaril • cytochrome P450 • CYP3A

Address for reprints: Joseph S. Bertino, Jr, PharmD, FCP, ORI Drug Development Center, Ordway Research Institute, Inc, 150 New Scotland Avenue, Albany, NY 12208.

This article has been cited by other articles:

				J. D. Ma, A. N. Nafziger, G. Rhodes, S. Liu, and J. S. Bertino Jr. DURATION OF PLECONARIL EFFECT ON CYTOCHROME P450 3A ACTIVITY IN HEALTHY ADULTS USING THE ORAL BIOMARKER MIDAZOLAM Drug Metab. Dispos., May 1, 2006; 34(5): 783 - 785. [Abstract] [Full Text] [PDF]