J Clin Pharmacol
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First published on February 26, 2009, doi:10.1177/0091270008331133

The Journal of Clinical Pharmacology 2009;49:398.

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©© 2009 American College of Clinical Pharmacology, Inc.
The Journal of Clinical Pharmacology, 10.1177/0091270008331133

Article

Effect of Different Durations of Ketoconazole Dosing on the Single-Dose Pharmacokinetics of Midazolam: Shortening the Paradigm

S. A. Stoch 1*, E. Friedman 1, A. Maes 1, K. Yee 1, Y. Xu 1, P. Larson 1, M. Fitzgerald 2, J. Chodakewitz 1, and J. A. Wagner 1

1 Merck and Co, Inc
2 ProMedica Clinical Research Center, Inc

* To whom correspondence should be addressed. E-mail: aubrey_stoch{at}merck.com.


  Abstract
Given the prominent role of cytochrome P450 3A (CYP3A) in the metabolism of drugs, it is critical to determine whether new chemical entities will be affected by the inhibition of this enzyme system and result in clinically relevant drug interactions. Ketoconazole interaction studies are frequently performed to determine a given compound’s sensitivity to CYP3A metabolism. The present study evaluated whether probing a sensitive substrate (midazolam) with a potent inhibitor (ketoconazole) at earlier time points (days 1 or 2) might be used to reliably gauge the magnitude of a meaningful interaction. The geometric mean ratios (ketoconazole + midazolamday 5/ketoconazole + midazolamday 1 and ketoconazole + midazolamday 5/ketoconazole + midazolamday 2) for midazolam AUC0-{infty} were 1.36 and 1.06 with corresponding 90% confidence intervals of (1.17, 1.57) and (0.83, 1.23), respectively. These findings suggest that short-term drug-drug interaction studies can predict the magnitude of change in AUC as reliably as studies using longer duration treatments.
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