Abstract
The objective of this study was to evaluate the duration of oral pleconaril (a picornavirus inhibitor) effect on intestinal and hepatic cytochrome P450 (P450) 3A activity as assessed by oral midazolam. Healthy adults received oral midazolam (0.075 mg/kg) on days 1 (baseline), 7, 9, 13, 20, 27, and 34. Oral pleconaril (400 mg) three times daily for 15 doses was administered on days 2 through 7. Blood samples were collected during each day of midazolam dosing to determine plasma midazolam concentrations. On days 5, 6, and 7, blood samples were collected to determine plasma pleconaril concentrations. Midazolam pharmacokinetics were determined by noncompartmental analyses, with bioequivalence assessed by least-squares geometric mean ratios (LS-GMR) and 90% confidence intervals (90% CI). Eighteen subjects completed the study. Midazolam Cmax (LS-GMR; 90% CI) decreased 24% on day 7 (0.76; 0.66–0.87). Midazolam oral clearance increased 53% on day 7 (1.53; 1.38–1.69). Midazolam oral clearance remained different on days 9 (1.38; 1.25–1.52) and 13 (1.19; 1.07–1.31) versus day 1. Midazolam volume of distribution (1.82; 1.57–2.11) and elimination half-life (1.19; 1.03–1.38) were also different on day 7 in comparison with day 1. Oral pleconaril increased intestinal and hepatic CYP3A activity. The duration of increased CYP3A activity by pleconaril was at least 6 days (but no longer than 13 days) after pleconaril discontinuation.
Footnotes
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Financial support was provided by ViroPharma, Incorporated.
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This work was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, September 14–17, 2003, Chicago, IL.
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J.S.B. has consulted for Viropharma, Inc., Ortho-McNeil, GlaxoSmithKline, and Merck. A.N.N. has consulted for Merck & Co. and Merck/Schering-Plough.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007831.
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ABBREVIATIONS: P450, cytochrome P450; AUC0-last, area under the concentration-time curve extrapolated to the last measurable concentration; AUC0-∞, area under the concentration-time curve extrapolated to infinity; CL, clearance; LS-GMR, least squares geometric mean ratios; 90% CI, 90% confidence interval(s).
- Received October 12, 2005.
- Accepted February 1, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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