An evaluation of the drug interaction potential of netupitant with substrates, inhibitor and inducer of CYP3A4.

Abstract

e19533 Background: Neurokinin-1 receptor antagonist (NK1 RA) is commonly administered in combination with a 5-HT3 RA such as palonosetron (PALO) to prevent the stimulus of nausea and vomiting caused by emetogenic chemotherapy. Netupitant (NETU), a new NK1 RA under evaluation for its antiemetic efficacy and tolerability, is both a substrate for and a competitive inhibitor of CYP3A4. Two studies were designed to determine the potential risk for drug-drug interaction in clinical practice. In the first study, the effects of NETU on the metabolism of two representative CYP3A4 substrates, erythromycin (ERY) and midazolam (MID) were determined. In the second study, a CYP3A4 inhibitor, ketoconazole (KETO), or an inducer, rifampicin (RIF) was coadministered with a fixed dose combination of NETU/PALO to observe the potential effects on NETU and PALO metabolism. Methods: Serial blood samples were collected from healthy volunteers and pharmacokinetic (PK) parameters were determined in both studies. The first trial was a 3-period crossover performed in 20 subjects receiving NETU (300 mg), ERY (500 mg) or MID (7.5 mg). The second trial was a 2-way crossover in 36 subjects receiving a single dose of NETU/PALO (300 mg/0.5mg, Day 1) administered as a fixed dose combination and KETO (400 mg QD, from Day-2 to Day 10) or RIF (600 mg QD from Day -7 to Day 10). Results: NETU, by inhibiting the CYP3A4, increased Cmax and AUC parameters by 40% and 130%, respectively, when administered with MID and by 30% when administered with ERY. KETO increased NETU AUC by 140% and Cmax by 25%, while RIF decreased NETU AUC by 83% and Cmax by 62%. A decrease of 19% was observed in PALO AUC when administered with RIF, while KETO had no relevant effect on PALO PK. Conclusions: The results of these studies suggest that the coadministration of NETU with drugs that are substrates, inhibitors, or inducers of the CYP3A4 enzymes, may require dose adjustments. These results are in line with pharmacokinetic data of aprepitant, the only commercially available NK1 RA. The effect of RIF on PALO is not considered clinically relevant. Treatments were well tolerated in all studies.