title: Pharmacokinetics of oral dexamethasone and midazolam when administered with single-dose intravenous 150 mg fosaprepitant in healthy adult subjects.
abstract: 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.
authors.affiliation: Orlando Clinical Research Center, Orlando, FL 32809, USA. tmarbury@ocrc.net
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Marbury
authors.forename: Phung L
authors.initials: PL
authors.lastname: Ngo
authors.forename: Craig R
authors.initials: CR
authors.lastname: Shadle
authors.forename: Bo
authors.initials: B
authors.lastname: Jin
authors.forename: Deborah
authors.initials: D
authors.lastname: Panebianco
authors.forename: Luzelena
authors.initials: L
authors.lastname: Caro
authors.forename: Jack
authors.initials: J
authors.lastname: Valentine
authors.forename: Gail
authors.initials: G
authors.lastname: Murphy
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000932:Antiemetics / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000077608:Aprepitant; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003907:Dexamethasone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009025:Morpholines / Q000008:administration & dosage*; D064729:Neurokinin-1 Receptor Antagonists; D055815:Young Adult
chemical_list: D000932:Antiemetics; D065692:Cytochrome P-450 CYP3A Inhibitors; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D000077608:Aprepitant; C579707:fosaprepitant; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam