Rolapitant is a novel NK1 receptor antagonist that maintains >90% receptor binding up to five days after a single 180-mg dose.
Lisa HolleOn September 2, 2015, FDA approved rolapitant (Varubi; Tesaro) in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.
Chemotherapy-induced nausea and vomiting can be a severely debilitating side effect of cancer therapy that can impair quality of life, functional ability, and treatment adherence. Without appropriate prophylaxis, moderately emetogenic chemotherapy can induce nausea and vomiting in 30% to 90% of patients; highly emetogenic chemotherapy can induce nausea and vomiting in more than 90% of patients. Nausea and vomiting can last up to five days after initiation of chemotherapy and is divided into two phases, acute (0-24 hours) and delayed (24-120 hours).
The activation of the substance P/neurokinin 1 (NK1) receptor signaling pathway is thought to be the primary mediator of nausea and vomiting in the delayed phase. Rolapitant is a novel NK1 receptor antagonist that maintains >90% receptor binding up to five days after a single 180 mg dose. In addition, rolapitant does not inhibit or induce cytochrome P450 (CYP)-3A4 and may provide an alternative with fewer potential drug interactions that the other approved NK1 receptor antagonists.
The rolapitant approval was based on data from three double-blind, randomized, active-controlled trials. Studies 1 and 2 evaluated 1,070 patients receiving their first cycle of highly emetogenic cisplatin-based chemotherapy, while study 3 evaluated 1,332 patients receiving their first cycle of moderately emetogenic chemotherapy (or an anthracycline plus cyclophosphamide).
In each of these studies, patients were given rolapitant 180 mg or placebo orally one to two hours before initiation of chemotherapy, and all patients received active control. In studies 1 and 2, active control consisted of intravenous granisetron (10 mcg/kg) plus oral dexamethasone (20 mg) 30 minutes before chemotherapy initiation, and twice-daily oral dexamethasone (8 mg) on days 2 through 4. In study 3, active control consisted of oral granisetron (2 mg) plus oral dexamethasone (20 mg) 30 minutes before chemotherapy initiation, and oral granisetron (2 mg) on days 2 and 3.
Efficacy was measured as percentage of patients with a complete response in the delayed phase, defined as no emesis or use of rescue medications for 24 to 120 hours after the initiation of chemotherapy. Researchers assessed endpoint results using daily diaries patients maintained over the 120-hour study period.
In the pooled analysis of studies 1 and 2, 71% of patients in the rolapitant group achieved a complete response, compared with 60% in the active control group (OR 1.6, 95% CI 1.3-2.1; P=0.0001). In the third study, 71% in the rolapitant group achieved complete response, compared with 62% in the active control group (OR 1.6, 95% CI 1.2-2.0; P=0.0002).
Patients tolerate rolapitant very well. The most common adverse events reported in the studies were dyspepsia, headache, constipation, hiccups, fatigue, and dizziness, occurring in <3% of patients. It is important to note that the inhibitory effects of rolapitant on P450 cytochrome (CYP)-2D6 can last at least seven days with a single dose.
Concomitant use of rolapitant in patients receiving thioridazine is contraindicated, due to QT prolongation and Torsades de Pointes risks. Rolapitant should be avoided in patients receiving pimozide, which may result in QT prolongation as well.
Rolapitant inhibits breast-cancer-resistance protein and p-glycoprotein. If concomitant use cannot be avoided, monitor for adverse effects related to the concomitant drug. Strong CYP3A4 inhibitors may decrease the efficacy of rolapitant, a CYP3A4 substrate. The safety of rolapitant has not been established in pediatric patients, pregnancy, and women who are breastfeeding.
Rolapitant is supplied in 90-mg tablets. The recommended dosing for moderately or highly emetogenic chemotherapy is 180 mg taken orally one to two hours before chemotherapy.
Dexamethasone and a seratonin (5-HT3) receptor antagonist (e.g. ondansetron) should be administered in combination with rolapitant; recommended dosing regimens can be found in the full prescribing information. No dose adjustments are required for renal or hepatic failure, but use should be avoided in severe hepatic impairment. Due to its long half-life (~7 days), rolapitant 180 mg should not be taken more than once every 14 days.