Rolapitant is a selective and long-acting
neurokinin-1 receptor antagonist approved in an oral formulation in combination with other
antiemetic agents for the prevention of delayed
chemotherapy-induced
nausea and
vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of
rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral
digoxin (0.5 mg) or
sulfasalazine (500 mg), probe substrates for the
P-glycoprotein (P-gp) and
breast cancer resistance
protein (BCRP), respectively. Administration of intravenous
rolapitant with the substrates did not result in clinically significant effects on
digoxin and
sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49-1.95) and 30% (GMR, 1.30; 90%CI, 1.19-1.42), respectively, when
rolapitant was coadministered orally with
digoxin compared with
digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02-2.86) and 127% (GMR, 2.27; 90%CI, 1.94-2.65), respectively, when
rolapitant was given orally with
sulfasalazine compared with
sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of
rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously,
rolapitant was safe and well tolerated. Patients taking oral
rolapitant with P-gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.