An open-label, balanced, 2-period crossover study to investigate the influence of aprepitant on docetaxel pharmacokinetics

2094 Background: Several cancer chemotherapeutic agents are metabolized by CYP3A4. Co-administration of compounds that inhibit CYP3A4 may lead to decreased metabolic clearance, increased exposure, and increased toxicity of these antineoplastic agents. Aprepitant (EMEND), a recently approved antiemetic agent, moderately inhibits human CYP3A4 in vivo and in vitro (Ki of ∼10 uM). To determine if aprepitant affects the pharmacokinetics of chemotherapeutic agents metabolized by CYP3A4, this study examined the effect of aprepitant on docetaxel, which is cleared largely by CYP3A4 metabolism. Methods: Ten patients at 3 investigative sites were given the same dose of docetaxel (DOC) monotherapy (60 to 100 mg/m2) on two separate occasions (∼3 weeks apart). In one of the cycles, patients received aprepitant (APR) 125 mg PO 1 hour prior to docetaxel infusion, followed on Days 2 and 3 with a single oral aprepitant dose of 80 mg. On the alternate treatment, they received docetaxel alone. The pharmacokinetic profile of docetaxel was determined for 30 hours following docetaxel infusion in both periods. Results: The pharmacokinetic parameters of docetaxel are summarized in the table below. Docetaxel pharmacokinetics were not affected by coadministration of aprepitant. No difference in toxicity was noted in the two chemotherapy cycles: mean absolute neutrophil count nadirs were 0.96 x 109/L with aprepitant and 0.85 x 109/L without aprepitant. Conclusions: Aprepitant has no effect on docetaxel pharmacokinetics or toxicity. Moderate inhibitors of CYP3A4 metabolism such as aprepitant are unlikely to have significant clinical effects on chemotherapeutic agents metabolized by CYP3A4. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck & Co., Inc. Merck & Co., Inc. Merck & Co., Inc. Merck & Co., Inc. Merck & Co., Inc.