title: Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers.
abstract: To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2-3). For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.
authors.affiliation: Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA.
authors.forename: Susie Xiujiang
authors.initials: SX
authors.lastname: Li
authors.forename: Edward
authors.initials: E
authors.lastname: Pequignot
authors.forename: Deborah
authors.initials: D
authors.lastname: Panebianco
authors.forename: Paul
authors.initials: P
authors.lastname: Lupinacci
authors.forename: Anup
authors.initials: A
authors.lastname: Majumdar
authors.forename: Laura
authors.initials: L
authors.lastname: Rosen
authors.forename: Tuli
authors.initials: T
authors.lastname: Ahmed
authors.forename: Jane E
authors.initials: JE
authors.lastname: Royalty
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rushmore
authors.forename: M Gail
authors.initials: MG
authors.lastname: Murphy
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Petty
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000932:Antiemetics / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000077608:Aprepitant; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011807:Quinolizines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012016:Reference Values; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000932:Antiemetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D009025:Morpholines; D011807:Quinolizines; D012702:Serotonin Antagonists; D000077608:Aprepitant; C060344:dolasetron; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C110718:hydrodolasetron