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The Effect of Oral Pleconaril on Hepatic Cytochrome P450 3A Activity in Healthy Adults Using Intravenous Midazolam as a Probe
Author(s) -
Ma Joseph D.,
Nafziger Anne N.,
Rhodes Gerry,
Liu Siyu,
Gartung Anne M.,
Bertino Joseph S.
Publication year - 2006
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270005283286
Subject(s) - midazolam , cyp3a , pharmacokinetics , pharmacology , oral administration , chemistry , medicine , cytochrome p450 , metabolism , sedation
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.