DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on February 7, 2006; DOI: 10.1124/dmd.105.007831

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.007831v1
34/5/783    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ma, J. D
Right arrow Articles by Bertino, J. S
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ma, J. D
Right arrow Articles by Bertino, J. S


Received for publication October 18, 2005.
Revised January 5, 2006.
Accepted for publication February 1, 2006.

Duration of Pleconaril Effect on Cytochrome P450 3A Activity in Healthy Adults Using the Oral Biomarker Midazolam

Joseph D Ma 1, Anne N Nafziger 2, Gerry Rhodes 3, Siyu Liu 4, Joseph S Bertino 2*

1 Amgen, Inc. 2 Ordway Research Institute 3 Gilead 4 Teva Neurosciences

* Address correspondence to: E-mail: sbertino{at}ix.netcom.com

Abstract

The objective of this study was to evaluate the duration of oral pleconaril (a picornavirus inhibitor) effect on intestinal and hepatic cytochrome P450 (CYP) 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 to 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.


Key words: CYP induction, CYP3A


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
O. A. Fahmi, S. Boldt, M. Kish, R. S. Obach, and L. M. Tremaine
PREDICTION OF DRUG-DRUG INTERACTIONS FROM IN VITRO INDUCTION DATA: Application of the Relative Induction Score Approach Using Cryopreserved Human Hepatocytes
Drug Metab. Dispos., September 1, 2008; 36(9): 1971 - 1974.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.