Population Pharmacokinetics of Rolapitant in Patients With Chemotherapy‐Induced Nausea and Vomiting

Population pharmacokinetics of rolapitant and its active metabolite M19 were studied in 482 patients receiving this neurokinin‐1 receptor antagonist in combination with a 5‐hydroxytryptamine‐3 receptor antagonist and dexamethasone for prevention of chemotherapy‐induced nausea and vomiting (CINV). Patients received a single dose of rolapitant (range, 9–180 mg) before administration of moderately or highly emetogenic chemotherapy. Population pharmacokinetic analysis was performed via nonlinear mixed‐effects modeling. Rolapitant pharmacokinetics was best characterized by a 2‐compartment model. Population typical values were estimated to be 0.962 L/h for apparent oral clearance and 214 L for central compartment volume of distribution. The intercompartment clearance and peripheral compartment volume of distribution was estimated to be 2.79 L/h and 164 L, respectively. Metabolite M19 pharmacokinetics was described by a 1‐compartment model with an apparent metabolite clearance of 1.83 L/h. Intersubject variability was moderate for pharmacokinetics parameters. Weight positively correlated with central compartment volume of distribution and peripheral compartment volume of distribution but not with apparent oral clearance. No other demographic, clinical, or pathophysiologic covariates, including liver and renal function, influenced rolapitant pharmacokinetics. A slight positive trend was observed between rolapitant exposure and efficacy (ie, complete response defined as no emesis and no use of rescue medication) in the delayed phase of CINV (>24–120 hours after chemotherapy). This further supports the 180‐mg dose of rolapitant in CINV patients. In summary, this validated population pharmacokinetic model satisfactorily describes pharmacokinetics of rolapitant and M19 in patients with CINV. These results support the recommendation that no dose adjustment for patient variables investigated is necessary.