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0091270008331133v1
49/4/398    most recent
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DRUG INTERACTIONS

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

S. A. Stoch, MD, E. Friedman, MS, A. Maes, PhD, K. Yee, PhD, Y. Xu, PhD, P. Larson, MS, M. Fitzgerald, MD, J. Chodakewitz, MD and J. A. Wagner, MD, PhD

From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Stoch, E. Friedman, Dr Maes, Dr Yee, Dr Xu, P. Larson, Dr Chodakewitz, Dr Wagner) and ProMedica Clinical Research Center, Inc, Boston, Massachusetts (Dr Fitzgerald).

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.

Key Words: Midazolam • ketoconazole • drug-drug interactions • cytochrome P450 3A

Address for reprints: S. Aubrey Stoch, MD, Merck & Co, Inc, RY34-A500, PO Box 2000, Rahway, NJ 07065-0900; e-mail: aubrey_stoch{at}merck.com.


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