Lack of Effect of Aprepitant on Hydrodolasetron Pharmacokinetics in CYP2D6 Extensive and Poor Metabolizers

• Published in: Journal of clinical pharmacology Vol. 46; no. 7; pp. 792 - 801
• Main Authors: Li, Susie Xiujiang, Pequignot, Edward, Panebianco, Deborah, Lupinacci, Paul, Majumdar, Anup, Rosen, Laura, Ahmed, Tuli, Royalty, Jane E., Rushmore, Thomas H., Murphy, M. Gail, Petty, Kevin J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-2006; SAGE Publications; Sage Publications, Inc
• Subjects: Administration, Oral; Adult; Antiemetics; Antiemetics - administration & dosage; Antiemetics - adverse effects; Antiemetics - pharmacology; Aprepitant; Complications and side effects; Cross-Over Studies; CYP2D6; CYP3A4; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; dolasetron; Dosage and administration; Drug metabolism; Electrocardiography; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacology; Evaluation; Female; Genotype; Humans; Indoles - administration & dosage; Indoles - adverse effects; Indoles - pharmacokinetics; interaction; Male; Middle Aged; Morpholines - administration & dosage; Morpholines - adverse effects; Morpholines - pharmacology; Pharmacokinetics; Quinolizines - administration & dosage; Quinolizines - adverse effects; Quinolizines - pharmacokinetics; Reference Values; Serotonin Antagonists - administration & dosage; Serotonin Antagonists - adverse effects; Serotonin Antagonists - pharmacokinetics; United States
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270006288954

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‐∞) 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‐∞, 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.