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Pharmacokinetics of Aprepitant After Single and Multiple Oral Doses in Healthy Volunteers

From Merck Research Laboratories, West Point and Blue Bell, Pennsylvania (Dr Majumdar, Ms Howard, Dr Goldberg, Ms Hickey, Mr Constanzer, Dr Rothenberg, Ms Crumley, Ms Panebianco, Dr Bradstreet, Dr Bergman, Dr Petty), and Brussels, Belgium (Dr De Lepeleire, Ms Michiels); Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Waldman, Dr Greenberg, Dr Butler); and SGS Biopharma, Centrum Ziekenhuis Antwerpen, Campus Stuivenberg, Belgium (Dr Knops).

Aprepitant is the first NK₁ receptor antagonist approved for use with corticosteroids and 5HT₃ receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (IV) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

Key Words: Aprepitant • pharmacokinetics • bioavailability, food effect

Address for reprints: Anup K. Majumdar, WP75B-100, Merck & Co, Sumneytown Pike, West Point, PA 19486.

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