Fosnetupitant

In preregistration clinical trials of the fixed combination of fosnetupitant and palonosetron, serum aminotransferase elevations occurred in a similar proportion of treated patients as controls receiving cancer chemotherapy. The aminotransferase elevations were transient, mild-to-moderate in severity, and not associated with symptoms or jaundice. The elevations were more likely due to the cancer chemotherapy than the antiemetic prophylaxis. There have been no convincing cases of clinically apparent liver injury attributable to fosnetupitant with palonosetron published in the literature and thus, significant liver injury must be exceedingly rare if it occurs at all.

In the combination drug, Akynzeo, palonosetron prevents nausea and vomiting during the acute phase and fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy. Neurokinin-1 (NK-1) inhibitor drugs, such as netupitant, possess unique anxiolytic, antidepressant, and antiemetic properties.

The fosnetupitant in this drug combination is a selective P/neurokinin-1 (NK-1) receptor antagonist. [Netupitant], the active moiety of fosnetupitant, is a selective neurokinin 1 (NK1) receptor antagonist with antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which results in the prevention of chemotherapy-induced nausea and vomiting (CINV). Substance P is found in neurons of vagal afferent fibers innervating the brain-stem nucleus tractus solitarii and the area postrema, which contains the chemoreceptor trigger zone (CTZ), and may be present at high levels in response to chemotherapy. The NK-receptor is a G-protein receptor coupled to the inositol phosphate signal-transduction pathway and is found in both the nucleus tractus solitarii and the area postrema. Netupitant demonstrated 92.5% NK1 receptor occupancy at 6 hours, with 76% occupancy at 96 hours.

Fosnetupitant is the prodrug of [netupitant]. Netupitant is a moderate inhibitor and substrate of CYP3A4. Akynzeo should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 systems. One dose of netupitant 300 mg significantly inhibits CYP3A4 for about 6 days. It is avisable to avoid concomitant use of drugs that are CYP3A4 substrates for one week. If not possible, consider dose reduction of CYP3A4 substrates. In the human, rat, dog, minipig and marmoset liver microsomal incubations, two major metabolites, an _N-demethylation product (M1) _and an _N-oxidation product (M2)_, in addition to hydroxylation products (M3), were identified in all species. CYP3A4 was found to be responsible for the oxidation of netupitant to the same metabolites observed also in the incubations with human liver microsomes. Metabolism was extensive, with the metabolites generally achieving greater concentrations than parent drug witin 24 hours. M1 and M2 exposure was similar in rat to humans, but higher in dogs, however M3 was lower in both species than in humans.