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

From the Merck Research Laboratories, West Point, Pennsylvania (Dr Li, Ms Panebianco, Dr Majumdar, Dr Rosen, Ms Ahmed, Dr Rushmore, Dr Murphy, Dr Petty); Thomas Jefferson University, Philadelphia, Pennsylvania (Mr Pequignot); Villanova University, Villanova, Pennsylvania (Dr Lupinacci); and West Pharmaceuticals Services, GFI Research, Evansville, Indiana (Dr Royalty).

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 (AUC_0-) and peak plasma concentration (C_max), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC_0-, 1.09 [90% CI, 1.01-1.18], C_max, 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.

Key Words: Aprepitant • dolasetron • interaction • CYP3A4 • CYP2D6

Address for reprints: Laura Rosen, MD, PhD, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486; e-mail: laura_rosen{at}merck.com.

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