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Pharmacokinetics of Oral Dexamethasone and Midazolam When Administered With Single‐Dose Intravenous 150 mg Fosaprepitant in Healthy Adult Subjects
Author(s) -
Marbury Thomas C.,
Ngo Phung L.,
Shadle Craig R.,
Jin Bo,
Panebianco Deborah,
Caro Luzelena,
Valentine Jack,
Murphy Gail
Publication year - 2011
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270010387792
Subject(s) - midazolam , pharmacokinetics , medicine , dexamethasone , anesthesia , pharmacology , sedation
Aprepitant or its prodrug fosaprepitant, in combination with a corticosteroid and a 5‐HT 3 receptor antagonist, are used to prevent chemotherapy‐induced nausea and vomiting. This study evaluated the effect of fosaprepitant 150 mg on CYP3A4 metabolism. Fosaprepitant 150 mg has been submitted to regulatory agencies for consideration of approval as a single‐day alternative to the 3‐day oral aprepitant antiemetic regimen currently marketed. Part 1 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral dexamethasone (8 mg daily for 3 days). Part 2 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral midazolam (2 mg on days 1 and 4). Thirteen subjects were enrolled in part 1 and 10 in part 2. For dexamethasone, fosaprepitant increased the area under the plasma concentration—time curve from 0 to 24 hours by approximately 2.0‐fold on days 1 and 2 and to a lesser extent (∼1.2‐fold) on day 3. Similarly, for midazolam, fosaprepitant increased the area under the plasma concentration—time curve from 0 hours to infinity by approximately 1.8‐fold on day 1 but had no effect on midazolam pharmacokinetics on day 4. Fosaprepitant 150 mg is a weak inhibitor of CYP3A4. Oral dexamethasone doses on days 1 and 2 should be reduced by approximately 50% when coadministered with intravenous fosaprepitant 150 mg on day 1.