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

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.

Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives.

OBJECTIVES: Neurokinin-1 receptor antagonists (NK1 RAs) are commonly coadministered with a 5-HT3 RA such as palonosetron to prevent nausea and vomiting induced by chemotherapy. Netupitant, a new highly selective NK1 RA, is both a substrate for and a moderate inhibitor of CYP3A4. Three studies were designed to evaluate the potential drug-drug interaction of netupitant with palonosetron and of the fixed dose combination of netupitant and palonosetron, NEPA, with an inhibitor (ketoconazole), an inducer (rifampicin) and a substrate (oral contraceptives) of CYP3A4. METHODS: Study 1 was a three-way crossover in 18 healthy subjects receiving netupitant alone, palonosetron alone, and the combination of both antiemetics. Studies 2 and 3 were two-way crossover trials where healthy subjects received NEPA (the fixed dose combination of netupitant and palonosetron). In study 2, 36 subjects received NEPA alone (day 1) and in combination with ketoconazole or rifampicin. In study 3, 24 healthy women received ethinylestradiol/levonorgestrel alone or in combination with NEPA (day 1). RESULTS: There were no significant pharmacokinetic interactions between netupitant and palonosetron. Ketoconazole increased netupitant area under curve (AUC) by 140 % and C max by 25 %. Rifampicin decreased netupitant AUC by 83 % and C max by 62 %. NEPA did not significantly affect exposure to ethinylestradiol, while systemic exposure to levonorgestrel increased by 40 %, but this was not considered clinically relevant. CONCLUSIONS: There were no clinically relevant interactions between netupitant and palonosetron, or between NEPA and oral contraceptives. The coadministration of NEPA with inhibitors or inducers of CYP3A4 may require dose adjustments. Treatments were well tolerated.

Evaluation of the effect of food and age on the pharmacokinetics of oral netupitant and palonosetron in healthy subjects: A randomized, open-label, crossover phase 1 study.

Antiemetic treatment compliance is important to prevent chemotherapy-induced nausea and vomiting, a feared chemotherapy side effect. NEPA, a new oral fixed combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a second-generation 5-HT3 RA, targets dual antiemetic pathways with a single dose. This study investigated the effect of food intake and age on NEPA pharmacokinetics (PK) and safety. In this open-label, single-center, randomized, phase 1 study, 24 adults (18-45 years) received NEPA in a fed or fasted state during the first treatment period and in the alternative state in the next treatment period. Twelve elderly subjects (≥65 years) received NEPA in a fasted state. Blood samples were taken for netupitant and palonosetron PK analysis. In the fed condition, netupitant plasma exposure increased, whereas palonosetron PK parameters were not affected. Furthermore, elderly subjects showed increased netupitant and palonosetron exposure compared with adults. All adverse events were mild/moderate, with constipation and headache the most common. Although food intake and age altered NEPA PK, dose adjustments were not needed, as netupitant and palonosetron exposure increases did not lead to safety concerns in healthy subjects.

Netupitant PET imaging and ADME studies in humans.

Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy-induced nausea and vomiting. Two studies were conducted to evaluate the brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography (PET) imaging with the NK1 receptor-binding-selective tracer [(11) C]-GR205171 was used to evaluate the brain penetration of different doses of netupitant (100, 300, and 450 mg) and to determine the NK1 -RO duration. A NK1 -RO of 90% or higher was achieved with all doses in the majority of the tested brain regions at Cmax, with a long duration of RO. The netupitant minimal plasma concentration predicted to achieve a NK1 -RO of 90%, C90% , in the striatum was 225 ng/mL; after administration of netupitant 300 mg, concentrations exceeded the C90% . In the ADME study, a single nominal dose of [(14) C]-netupitant 300 mg was used to assess its disposition. Absorption was rapid and netupitant was extensively metabolized via Phase I and II hepatic metabolism. Elimination of >90% was predicted at day 29 and was principally via hepatic/biliary route (>85%) with a minor contribution of the renal route (<5%). In conclusion, these studies demonstrate that netupitant is a potent agent targeting NK1 receptors with long lasting RO. In addition, netupitant is extensively metabolized and is mainly eliminated through the hepatic/biliary route and to a lesser extent via the kidneys.

The virosomal adjuvanted influenza vaccine.

IMPORTANCE OF THE FIELD: The protection conferred by influenza vaccines varies for several reasons, for example the age or degree of immune depression of the recipient. All currently available seasonal influenza vaccines are safe and substantially effective in preventing influenza in healthy people. However, elderly people and patients with chronic diseases or immune system defects need a more effective vaccine to avoid serious risks from influenza and its complications. Research has been undertaken to improve the efficacy of vaccination. Recent research includes the use of new adjuvants or antigen-presenting strategies. AREAS COVERED IN THIS REVIEW: The virosomal adjuvanted subunit influenza vaccine has been studied in groups for whom vaccination is recommended. We describe virosomal technology, including production and mode of action, as well as the available efficacy, immunogenicity and safety data, with the aim of understanding the benefits of this vaccine's use. WHAT THE READER WILL GAIN: A review of published data on efficacy, immunogenicity and safety from sponsor- and investigator- driven studies, focusing on recent publications. TAKE HOME MESSAGE: The vaccine was generally very immunogenic and safe in all investigated populations. Its ability to induce protective antibody titers has been shown to exceed that of conventional influenza vaccines in elderly people and individuals with little or no prior exposure to the viral strains.