The effect of oral pleconaril on hepatic cytochrome P450 3A activity in healthy adults using intravenous midazolam as a probe

J Clin Pharmacol. 2006 Jan;46(1):103-8. doi: 10.1177/0091270005283286.

Abstract

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-infinity) 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-infinity) and systemic clearance suggest that oral pleconaril increased hepatic CYP3A activity in healthy adults.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Female
  • Humans
  • Injections, Intravenous
  • Liver / drug effects*
  • Liver / enzymology
  • Male
  • Midazolam / administration & dosage
  • Midazolam / pharmacokinetics*
  • Oxadiazoles / administration & dosage
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology*
  • Oxazoles

Substances

  • Antiviral Agents
  • Oxadiazoles
  • Oxazoles
  • Cytochrome P-450 Enzyme System
  • pleconaril
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Midazolam