Duration of pleconaril effect on cytochrome P450 3A activity in healthy adults using the oral biomarker midazolam.
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 C(max) (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.
Ma
Joseph D
JD
Amgen, Inc., Thousand Oaks, California, USA.
Nafziger
Anne N
AN
Rhodes
Gerry
G
Liu
Siyu
S
Bertino
Joseph S
JS
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008874:Midazolam / Q000097:blood*; D008875:Middle Aged; D010069:Oxadiazoles / Q000494:pharmacology*; D010080:Oxazoles
D000998:Antiviral Agents; D006993:Hypnotics and Sedatives; D010069:Oxadiazoles; D010080:Oxazoles; C115201:pleconaril; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam