Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of midazolam, erythromycin, and dexamethasone

Abstract

The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.

Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC)

“…Rolapitant differs from existing NK-1 receptor antagonists, as it is neither an inhibitor nor inducer of CYP P450 3A4 (CYP3A4) and, thus, is unlikely to produce clinically important drug-drug interactions [28,33,34]. The NK-1 receptor antagonist aprepitant, the prodrug fosaprepitant, and the netupitant combination with palonosetron inhibit or induce CYP3A4 [17,18].…”

A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy

“…Due to the increased exposure to DEX when given in combination with NETU [9], the DEX dose in the NEPA group was reduced to achieve DEX exposure similar to that in the PALO group. The 0.50 mg oral PALO dose was selected based on a noninferiority efficacy trial evaluating three oral PALO doses, 0.25, 0.50 and 0.75 mg, compared with i.v.…”

Netupitant/Palonosetron

“…The pharmacokinetics of netupitant were not affected by the presence of midazolam. 1,26 Caution should be used when administering netupitant/palonosetron with benzodiazepines metabolized via CYP3A4 (eg, alprazolam, midazolam, triazolam). 1 Coadministration of netupitant and erythromycin increased erythromycin's C max by 30%, AUC inf by 30%, and mean half-life by 17%.…”

“…The pharmacokinetics of netupitant were not affected by the presence of erythromycin. 26 Coadministration of netupitant 300 mg and dexamethasone (20 mg on day 1 followed by 8 mg twice daily on days 2 to 4) increased dexamethasone's AUC 0-24 by 72% on day 1, AUC [24][25][26][27][28][29][30][31][32][33][34][35][36] by 143% on day 2, AUC 84-108 by 140%, and AUC 84-inf by 140% compared with dexamethasone alone. The C max of dexamethasone was increased by 11% on day 1, by 66% on day 2, and by 75% on day 4.…”

“…The pharmacokinetics of netupitant were not affected by the presence of dexamethasone. 1,26 A dosage reduction is recommended for dexamethasone. 1 Coadministration of netupitant/palonosetron with chemotherapeutic agents metabolized by CYP3A4 (eg, docetaxel, paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine) may increase the systemic exposure of these chemotherapeutic agents.…”