Drug–drug interaction profile of components of a fixed combination of netupitant and palonosetron: Review of clinical data

Abstract

Neurokinin-1 (NK1) receptor antagonists (RAs) are commonly coadministered with serotonin (5-HT3) RAs (e.g. palonosetron (PALO)) to prevent chemotherapy-induced nausea/vomiting. Netupitant/palonosetron (NEPA), an oral fixed combination of netupitant (NETU)—a new NK1 RA—and PALO, is currently under development. In vitro data suggest that NETU inhibits CYP3A4 and is a substrate for and weak inhibitor of P-glycoprotein (P-gp). This review evaluates potential drug–drug interactions between NETU or NEPA and CYP3A4 substrates/inducers/inhibitors or P-gp substrates in healthy subjects. Pharmacokinetic (PK) parameters were evaluated for each drug when NETU was coadministered with PALO (single doses) and when single doses of NETU or NEPA were coadministered with CYP3A4 substrates (erythromycin (ERY), midazolam (MID), dexamethasone (DEX), or oral contraceptives), inhibitors (ketoconazole (KETO)), or inducers (rifampicin (RIF)), or a P-gp substrate (digoxin (DIG)). Results showed no relevant PK interactions between NETU and PALO. Coadministration of NETU increased MID and ERY exposure and significantly increased DEX exposure in a dose-dependent manner; NETU exposure was unaffected. NEPA coadministration had no clinically significant effect on oral contraception, although levonorgestrel exposure increased. NETU exposure increased after coadministration of NEPA with KETO and decreased after coadministration with RIF; PALO exposure was unaffected. NETU coadministration did not influence DIG exposure. In conclusion, there were no clinically relevant interactions between NETU and PALO, or NEPA and oral contraceptives (based on levonorgestrel and ethinylestradiol exposure). Coadministration of NETU or NEPA with CYP3A4 inducers/inhibitors/substrates should be done with caution. Dose reduction is recommended for DEX. Dose adjustments are not needed for NETU coadministration with P-gp substrates.

Complementary Pharmacokinetic Profiles of Netupitant and Palonosetron Support the Rationale for Their Oral Fixed Combination for the Prevention of Chemotherapy‐Induced Nausea and Vomiting

“…These were similar to the values observed upon combined administration of netupitant and palonosetron (660 [49.4] ng/mL and 1.863 [26.1] ng/mL, respectively; Table ). Additionally, values of AUC inf and t 1/2 were similar across all study subjects, when netupitant or palonosetron was administered alone, as compared with combined netupitant and palonosetron administration (Table ).…”

“…After administration of a single dose of NEPA, alone or in combination with 400‐mg ketoconazole for 12 days, netupitant C max and AUC inf increased 1.2‐fold and 2.4‐fold, respectively. Following single‐dose NEPA combined with a daily administration of 600‐mg rifampicin for 17 days, netupitant C max and AUC inf decreased 2.2‐fold and 4.9‐fold, respectively …”

“…Following singledose NEPA combined with a daily administration of 600-mg rifampicin for 17 days, netupitant C max and AUC inf decreased 2.2-fold and 4.9-fold, respectively. 31 In vitro, netupitant proved to be a moderate inhibitor of CYP3A4. 32 In vivo, the exposure to the CYP3A4 substrates dexamethasone, erythromycin, and midazolam has been shown to increase upon coadministration with netupitant, whereas the exposure to the contraceptives ethinylestradiol and levonorgestrel was not affected by NEPA coadministration.…”

“…32 In vivo, the exposure to the CYP3A4 substrates dexamethasone, erythromycin, and midazolam has been shown to increase upon coadministration with netupitant, whereas the exposure to the contraceptives ethinylestradiol and levonorgestrel was not affected by NEPA coadministration. 31 Considering the likelihood of coadministration of netupitant and dexamethasone and the significant dose-dependent increase in dexamethasone exposure following coadministration with netupitant, it is recommended that oral doses of dexamethasone should be reduced by approximately 50% when given in combination with netupitant. 31 The potential for netupitant autoinhibition of CYP3A4 can be excluded because, in the clinical practice, NEPA is administered as a single-dose treatment per chemotherapy cycle.…”

“…31 Considering the likelihood of coadministration of netupitant and dexamethasone and the significant dose-dependent increase in dexamethasone exposure following coadministration with netupitant, it is recommended that oral doses of dexamethasone should be reduced by approximately 50% when given in combination with netupitant. 31 The potential for netupitant autoinhibition of CYP3A4 can be excluded because, in the clinical practice, NEPA is administered as a single-dose treatment per chemotherapy cycle. Absence of netupitant autoinhibition was also confirmed by a multiple-dose PK study in healthy subjects performed in the frame of a development program for an indication different than CINV.…”