Rolapitant is used in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT3 antagonist.
Contraindications
Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant. Under the European approval, it is contraindicated in combination with St. John's Wort, which is expected to accelerate inactivation of rolapitant.
Side effects
In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT3 antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT3 antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite, neutropenia, dizziness, indigestion and stomatitis.
Overdose
Up to eightfold therapeutic doses have been given in studies without problems.
Interactions
Rolapitant moderately inhibits the liver enzymeCYP2D6. Blood plasma concentrations of the CYP2D6 substratedextromethorphan have increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 and P-glycoprotein, which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%. Strong inducers of the liver enzymeCYP3A4 decrease the area under the curve of rolapitant and its active metabolite ; for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.
Pharmacology
Pharmacodynamics
Both rolapitant and its active metabolite M19 block the NK1 receptor with high affinity and selectivity: to block the closely related receptor NK2 or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.
Pharmacokinetics
Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins. It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 and a number of inactive metabolites. Rolapitant is mainly excreted via the feces in unchanged form, and to a lesser extent via the urine in form of its inactive metabolites. Elimination half-life is about seven days over a wide dosing range.
