Neurokinin-1 (NK-1) receptor antagonists are a new class of antiemetic drugs that possess unique anxiolytic, antidepressant, and antiemetic properties. The discovery of neurokinin-1 (NK-1) receptor blockers was a crucial point in the prevention of emesis associated with cancer chemotherapy.[1][2]

The neurokinin-1 receptor inhibitor class is one of the seven classes of drugs used to suppress nausea and vomiting in patients associated with cancer chemotherapy. The classes of antiemetic drugs are serotonin (5-HT) receptor antagonists, dopamine (D) receptor antagonists, histamine (H) receptor antagonists, neurokinin-1 receptor (NK-1) antagonists, antimuscarinics, cannabinoids, and corticosteroids. Patients’ development of nausea, vomiting, and vertigo may be due to pregnancy, during cancer chemotherapy, and motion sickness in a car, boat, or ship cruise. Some examples of the neurokinin-1 receptor inhibitor drug class are aprepitant, rolapitant, casopitant, netupitant, maropitant, and fosaprepitant. A new, highly selective NK-1 receptor antagonist, rolapitant, has an exceptionally long plasma half-life, T1/2 (180 hr), and it was FDA approved in September 2015 for the prevention of chemotherapy-induced delayed emesis.

Clinical Uses of Neurokinin-1 Receptor Antagonists:

Neurokinin-1 receptor (NK-1) antagonists such as aprepitant, rolapitant, casopitant, fosaprepitant, netupitant, and maropitant are effective to treat postsurgical nausea and vomiting, and cancer chemotherapy-induced nausea and vomiting. Fosaprepitant administration is via an intravenous (IV) formulation that is converted within 30 minutes to aprepitant after infusion. Aprepitant is available for administration orally or IV in multiple strengths. There is a combination of netupitant/palonosetron in an oral formulation. Casopitant is an investigational medication in development. Maropitant is an antiemetic in dogs and cats in the United States.

Off-Label Uses of Neurokinin-1 Receptor Antagonists:

There are currently no off-label uses for neurokinin-1 receptor antagonists reported.

NK-1 receptor antagonists have antinausea and anti-vomiting properties that get relayed through a central blockade in the area postrema, nucleus tractus solitarius, and visceral afferent nerves. NK-1 receptors mediate most of the central and peripheral effects of substance P. Substance P is an excitatory neurotransmitter that has a role in pain perception. It is among a class of neuropeptides called neurokinins. Its receptor, NK-1, is a G protein-coupled consisting of seven transmembrane helical elements. Therefore, NK-1 receptor antagonists can prevent both central and peripheral stimulation of vomiting centers. NK-1 receptor antagonists such as aprepitant (oral and IV formulations) are highly selective NK-1 receptor antagonists which cross the blood-brain barrier and occupy NK-1 receptors in the brain. Animal and human positron emission tomography (PET) studies with NK-1 receptor antagonists have shown that it crosses the blood-brain barrier and occupies brain NK-1 receptors. Aprepitant has no affinity for corticosteroid, serotonin, or dopamine receptors.

Nausea and vomiting associated with emetogenic chemotherapy have two components: a universally acute phase experienced within 24 hours after chemotherapy and a delayed phase that affects only some patients on days 2 through 5. Serotonin (5-HT3) receptor antagonists are not very effective against delayed emesis. However, inhibitors of the NK-1 receptors, i.e., the receptors for the neuropeptide substance P, such as aprepitant (and its parenteral formulation fosaprepitant), have antiemetic effects in delayed nausea and improve the efficacy of standard antiemetic regimens in patients receiving multiple cycles of chemotherapy.[3][4][5][6]

Pharmacodynamics/Pharmacokinetics

In the fasted state, and after a single oral dose of 40 mg of aprepitant, the mean area under the plasma concentration-time curve (AUC0-∞) is found to be 7.8 mcg x hr/mL, and the mean peak plasma concentration (Cmax) is 0.7 mcg/mL, observed at approximately 3 hours after dose administration (Tmax).

After a single 125 mg oral dose of aprepitant on day 1 and 80 mg once daily on days 2 and 3, the area under the curve (AUC) for 0-24 hr is found to be 19.6 mcg x hr/mL and 21.2 mcg x hr/mL on day 1 and day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were observed in approximately 4 hours (Tmax) on day 1 and day 3, respectively. Aprepitant pharmacokinetics is found to be non-linear across the clinical dose range. 

Route of Administration

Oral and IV for aprepitant, and IV for fosaprepitant.

The NK-1 receptor antagonist aprepitant is sometimes given with a 5-HT3 antagonist and a glucocorticoid, e.g., ondansetron and dexamethasone. Ralopitant and netupitant are oral formulations.

Onset of Action

For oral aprepitant, the onset of action is 1 hour, the peak blood concentration is 4 hours as published in the manufacturer’s package insert.

Duration of Action

The duration of action of aprepitant is 24 hours as published in the manufacturer’s package insert and other publications. According to the pharmacokinetic principle, it should take approximately 4 to 5 half-lives (T1/2) to eliminate most of the absorbed drug from the body. Therefore, one should expect the duration of action of aprepitant to be at least 40 hours.

Distribution

The volume of distribution of aprepitant is 70 liters.

The mean absolute oral bioavailability of aprepitant is approximately 60% to 65%.

Protein Binding

Protein binding for neurokinin-1 (NK-1) receptor antagonists, e.g., aprepitant is greater than 95%.

Metabolism

NK-1 receptor antagonists, such as aprepitant, is metabolized primarily by cytochrome P450 enzymes, e.g., CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Researchers have identified seven less active metabolites of aprepitant in human plasma.

Clearance

Apparent plasma clearance of aprepitant is 62 to 90 mL/min

Elimination Half-life

The biological half-life of aprepitant (neurokinin-1 (NK-1) receptor antagonist) is 9 to 13 hours. Aprepitant is eliminated primarily by metabolism through the liver; the kidneys do not excrete it.

Excretion

After a single administration of an intravenous 100 mg dose of radiolabeled [14C]-aprepitant in healthy subjects, 45% of the radioactivity was recoverable in feces and 57% in the urine. There was no study conducted with a radiolabeled capsule formulation. The results of excretion after oral and intravenous administration may differ.

Adverse Reactions: Severe

• Hives and rash
• Stevens-Johnson syndrome

Adverse Reactions: Mild

• Sleepiness
• Diarrhea
• Weakness
• Tiredness
• Constipation
• Gas
• Stomach pain
• Heartburn
• Nausea
• Hiccups
• Loss of appetite
• Headache
• Fever
• Itching
• Hair loss

Pregnancy

Do not take neurokinin-1 (NK-1) receptor antagonists if pregnant or planning to get pregnant or breastfeeding. During treatment with neurokinin-1 (NK-1) receptor antagonists, if a patient is on birth control medication, the patient should use an additional method of birth control to avoid unplanned or unwanted pregnancy. Additionally, the patient should continue with other pregnancy protection for one month after treatment with neurokinin-1 (NK-1) receptor antagonists, e.g., aprepitant. It was FDA classified as pregnancy Class B under the prior system for pregnancy classification.

Drug Interactions

Potential drug interactions can occur with neurokinin-1 (NK-1) receptor antagonists with concomitant medications because of changes in drug metabolism, e.g., CYP3A4 inhibition; this can occur in patients taking prescription and non-prescription medications, as well as herbal and nutritional supplements. The following is a list of potential drug interactions that may require drug monitoring or avoid combination: warfarin (monitor therapy); ivabradine (avoid combination); antifungals such as ketoconazole and itraconazole; lansoprazole; clarithromycin; diltiazem; carbamazepine; HIV protease inhibitors, such as ritonavir, and nelfinavir; hormonal contraceptives; nefazodone; oral steroids such as dexamethasone and methylprednisolone; paroxetine; phenytoin; cancer chemotherapy medications such as docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, tamoxifen, vinblastine, vincristine, and vinorelbine; rifampin; tolbutamide; and troleandomycin; benzodiazepines such as alprazolam, diazepam, midazolam, and triazolam.

Patients taking pimozide should not take neurokinin-1 (NK-1) receptor antagonists. Inhibition of CYP3A4 enzyme by neurokinin-1 (NK-1) receptor antagonists, e.g., aprepitant, could precipitate elevated plasma concentrations of pimozide, which is a CYP3A4 substrate. Drug interaction between pimozide and aprepitant could cause serious or life-threatening reactions, such as QTc prolongation which is a known adverse reaction of pimozide. Neurokinin-1 (NK-1) receptor antagonists, e.g., aprepitant, is also contraindicated with the following drugs: 

• Astemizole
• Cisapride
• Flibanserin
• Lomitapide
• Pimozide
• Terfenadine
• Ivabradine

Do not take neurokinin-1 (NK-1) receptor antagonists if pregnant or planning to get pregnant or breastfeeding. During treatment with neurokinin-1 (NK-1) receptor antagonist, if a patient is on birth control medication, the patient should use an additional method of birth control to avoid unplanned or unwanted pregnancy. Additionally, the patient should continue with other pregnancy protection for one month after treatment with neurokinin-1 (NK-1) receptor antagonists, e.g., aprepitant. It is also FDA classified as Pregnancy Class B.