Category: Professional Posters
Purpose: NEPA, fixed combination of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron, plus dexamethasone is recommended by guidelines for antiemetic prophylaxis following highly (HEC) and some moderately emetogenic chemotherapy. The IV NEPA (fosnetupitant 235 mg-palonosetron 0.25 mg) formulation was developed to improve its administration convenience. While palonosetron as single agent is administered as a 30-second bolus, IV NEPA is administered as a 30-minute infusion before chemotherapy. This study was performed to predict fosnetupitant (prodrug) and netupitant maximum plasma concentrations (Cmax) after single-dose IV NEPA at various infusion rates, and to develop safety considerations for shorter infusion durations.
Methods: Experimental pharmacokinetic (PK) data used for model predictions were obtained from a phase 1 study, Study 1 (EudraCT 2015-004750-18), in 24 HEC-treated patients receiving a single IV NEPA 30-minute infusion. Two- and three-compartment PK models for IV infusion were fitted to experimental fosnetupitant and netupitant plasma concentration-time data, respectively. Model-predicted fosnetupitant and netupitant PK curves were generated for 2-, 5-, 10-, 15-, and 30-minute fosnetupitant IV infusions. For safety considerations, simulated fosnetupitant and netupitant Cmax values were compared with experimental Cmax results from a phase 1 study, Study 2 (EudraCT 2012-003407-35), in 148 healthy volunteers receiving a single 30-minute infusion of IV fosnetupitant at doses ranging from 17.6 to 353 mg; safety and tolerability results from healthy volunteers in the fosnetupitant 353-mg dose (n=9) cohort were used.
Results: Two- and three-compartment PK models were suitable for best-fitting, respectively, experimental fosnetupitant and netupitant plasma concentration-time data after 30-minute IV fosnetupitant infusion, as shown by goodness-of-fit parameters. Model-predicted Cmax of netupitant following single-dose IV NEPA administration at 2-, 5-, 10-, 15-, and 30-minute infusion times was 898.5 ng/mL for 2-minute, 814.6 ng/mL for 5-minute, 717.9 ng/mL for 10-minute, 656.6 ng/mL for 15-minute, and 564.5 ng/mL for 30-minute infusions. Predicted Cmax for the 30-minute infusion duration matched the experimental mean (standard deviation [SD]) netupitant Cmax of 562.1 (181) ng/mL reached in Study 1 with IV NEPA 30-minute infusion in patients. For all modeled IV NEPA infusion times, netupitant Cmax was lower than the mean (SD) Cmax reached in Study 2 after 30-minute infusion of fosnetupitant 353 mg in healthy volunteers (1310  ng/mL), a dose at which no local or systemic drug-related adverse events of grade >1 occurred (grade 1 feeling hot, dyspnea, and orthostatic hypotension in 2 volunteers). Model-predicted fosnetupitant Cmax after 2- and 5-minute infusions was 15660 ng/mL and 12212 ng/mL, respectively; both exceeded the mean (SD) fosnetupitant Cmax observed in healthy volunteers following 353 mg fosnetupitant given over 30 minutes (9562  ng/mL).
Conclusion: Netupitant Cmax for all simulated infusion times was substantially lower than the experimental mean Cmax reached with the 353-mg dose of fosnetupitant 30-minute infusion, which was shown to be safe and well tolerated. Administration of IV NEPA over a shorter infusion duration may be feasible and could increase its convenience of administration. Validation of the data in a clinical trial is required.