An evaluation of the drug interaction potential of netupitant with digoxin.

Abstract

e19530 Background: The new, highly selective neurokinin-1 receptor antagonist netupitant (NETU) has been developed to provide protection from nausea and vomiting in patients receiving emetogenic chemotherapy. There is evidence from in vitro studies that NETU is a substrate for and a weak inhibitor of the P-glycoprotein (Pgp). Pgp plays a major role in the pharmacokinetics of digoxin (DIG), a cardiac glycoside with a narrow therapeutic index. The possible interaction between NETU and Pgp has been assessed by analysing the effect of NETU on DIG pharmacokinetics. Safety parameters have also been assessed. Methods: This study was an open-label, fixed-sequence design to evaluate the effect of NETU on DIG at steady state in 16 healthy volunteers (8 male and 8 female). A loading dose of 3 x 0.5 mg DIG (0.5 mg every 6 hours) was given on day 1, followed by a daily oral dose of 0.25 mg DIG for 11 consecutive days (days 2-12); NETU was administered as single oral dose of 450mg on day 8. Serial blood and urine samples were collected for the determination of the pharmacokinetic parameters. Physical examination, vital signs, electrocardiogram (ECG), adverse events, clinical chemistry, hematology, urinalysis, and overall tolerability were reported. Results: Based on the AUC(0-24h) parameter at steady-state, the extent of DIG exposure was not influenced by NETU coadministration. The confidence interval of Cmin was within the 80-125% equivalence limits, while the observed Cmax was slightly over 125%, which was not considered clinically relevant. The excretion of DIG in urine was 57% after NETU coadministration compared to 55% of DIG alone. There were no gender-specific differences in the extent of absorption (AUC) for DIG, and no safety-related influence of DIG or NETU was observed on safety and laboratory assessments, vital signs, or ECG parameters. Based on historical data NETU pharmacokinetics was not affected by DIG coadministration. Conclusions: No clinically relevant interactions occurred between NETU and DIG. The results of this study suggest that the coadministration of NETU with Pgp substrates may not require dose adjustments. Study treatments were well tolerated.