Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients
Purpose: Aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist approved for the treatment and prevention of emesis caused by moderately and highly emetogenic chemotherapy, is an inhibitor, inducer, and substrate of the cytochrome P450 3194 pathway. The CYP3A4 pathway is the major pathway of the metabolism of vinorelbine, a vinca alkaloid frequently used in combination with cisplatin. Therefore, we studied the potential interaction of the aprepitant 3-day antiemetic regimen on the pharmacokinetics of vinorelbine. Patients and methods: Fourteen patients with metastatic solid tumors were included in this open-label, balanced, 2-period crossover study. In treatment arm A, vinorelbine (25 mg/m2weekly) was administered alone, while in treatment arm B the same dose of vinorelbine was administered following the administration of the aprepitant antiemetic regimen on day 1 and alone on day 8. The antiemetic regimen of aprepitant was comprised of the following; on day 1:125 mg aprepitant, 12 mg dexamethasone, and 32 mg ondansetron; on days 2 and 3:80 mg aprepitant and 8 mg dexamethasone and on day 4:8 mg dexamethasone. Blood samples for vinorelbine pharmacokinetic analysis were collected over 96 h. Results: Two patients discontinued the study due to adverse events that were judged not to be drug-related. Complete pharmacokinetic data of vinorelbine administered alone and with the aprepitant antiemetic regimen were obtained in 12 patients. The mean plasma concentration profile of vinorelbine administered with aprepitant was identical to that following vinorelbine administered alone, with geometric mean vinorelbine plasma AUC ratios of treatment B day 1/treatment A day 1 and of treatment B day 8/treatment A day of 1.01 (0.93, 1.10) and 1.00 (0.92, 1.08), respectively. Conclusion: As the aprepitant antiemetic regimen has no detectable inhibitory or inductive effect on the pharmacokinetics of vinorelbine, aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone can be safely combined with vinorelbine at clinically recommended doses.