Netupitant

Netupitant is a potent and selective antagonist of the neurokinin 1 (NK1) receptor. It is used in combination with palonosetron, a 5-HT3 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV). The combination is known under the brand name Akynzeo. Netupitant, by blocking the action of substance P in the central nervous system (CNS), prevents nausea and vomiting associated with certain types of cancer chemotherapy.

Mechanism of Action

Netupitant acts by selectively inhibiting the neurokinin 1 (NK1) receptor, which is a key player in the vomiting reflex. Substance P, a natural neuropeptide, binds to NK1 receptors in the brain's vomiting center to induce vomiting. By blocking this interaction, netupitant effectively prevents the onset of nausea and vomiting. Its efficacy is enhanced when used in combination with palonosetron, which blocks the 5-HT3 receptors, another pathway involved in the vomiting reflex.

Pharmacokinetics

The pharmacokinetic profile of netupitant is characterized by a slow absorption and a long half-life, making it suitable for the prevention of both acute and delayed phases of CINV. It is extensively metabolized in the liver, primarily through the CYP3A4 enzyme, and its metabolites are excreted through both feces and urine. The presence of food does not significantly affect the absorption of netupitant, allowing it to be administered without regard to meals.

Clinical Use

Netupitant, in combination with palonosetron (as Akynzeo), is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. The combination has been shown to significantly improve the quality of life for patients undergoing chemotherapy by reducing the incidence and severity of CINV.

Adverse Effects

The most common adverse effects associated with netupitant/palonosetron combination include headache, constipation, fatigue, and asthenia. These side effects are generally mild to moderate in severity and transient in nature. As netupitant is metabolized by CYP3A4, it has the potential for drug-drug interactions with other substances metabolized by this enzyme. Therefore, caution should be exercised when it is co-administered with other CYP3A4 substrates, inhibitors, or inducers.

Regulatory Approval

Netupitant/palonosetron received approval from the United States Food and Drug Administration (FDA) in 2014 for use in adults. Subsequent approvals in other jurisdictions have followed, broadening its availability for patients worldwide.

Conclusion

Netupitant, particularly in combination with palonosetron, represents a significant advancement in the management of chemotherapy-induced nausea and vomiting. Its mechanism of action, targeting both NK1 and 5-HT3 receptors, addresses a broader range of pathways involved in CINV, offering enhanced protection for patients undergoing chemotherapy.