Antiemetic, Neurokinin-1 Receptor Blockers

Article Author:
Michael Ibrahim
Article Editor:
Scott Dulebohn
Updated:
6/1/2018 4:02:35 PM
PubMed Link:
Antiemetic, Neurokinin-1 Receptor Blockers

Indications

Neurokinin-1 (NK-1) inhibitors are a new class of antiemetic drugs which possess unique anxiolytic, antidepressant, and antiemetic properties. The discovery of Neurokinin-1 (NK-1) receptor blockers was a crucial point in the prevention of emetic associated with cancer chemotherapy.

Neurokinin-1 Receptor Inhibitors is one of the seven classes of drugs used to suppress nausea and vomiting in patients. The classes of these antiemetic drugs are serotonin (5-HT), dopamine (D), histamine (H), 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 antagonist, rolapitant, with an exceptionally long plasma half-life, T1/2 (180 hr) was FDA approved in September 2015 for prevention of chemotherapy-induced delayed emesis.

Clinical Uses of Neurokinin-1 Receptor Inhibitors:

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

Off-Label Uses of Neurokinin-1 Receptor Inhibitors:

No off-label uses for Neurokinin-1 receptor antagonist are reported.

Mechanism of Action

NK-1 receptor inhibitors have antinausea and anti-vomiting properties that are 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-type protein 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 (an oral and IV formulation) are highly selective NK-1 receptor inhibitors 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 that is 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, 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 (Aapro et al., 2015).

Administration

Pharmacodynamics/Pharmacokinetics

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

After an oral, single 125 mg dose of Aprepitant on Day 1 and 80 mg once daily on Days 2 and 3, the Area Under the Curve for 0-24hr is found to be 19.6 mcg/hr/mL and 21.2 mcg/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-HT antagonist and dexamethasone. Ralopitant and Netupitant are oral formulations

Onset of Action

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

Duration of Action

Duration of action of Aprepitant is 24 hours as published in manufacturer’s insert and other publications. According to pharmacokinetics principle, it should take approximately 4-5 Half-lives (T) 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

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 and Aprepitant is greater than 95%

Metabolism

NK-1 receptor inhibitors, such as Aprepitant, is metabolized primarily by Cytochrome enzymes, CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven weakly active metabolites of Aprepitant have been identified in human plasma.

Clearance

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

Elimination Half-life

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

Excretion

After a single administration of intravenous 100-mg dose of [14C]-aprepitant prodrug to healthy subjects, 45% of the radioactivity was recovered in feces and 57% in the urine. No study was not conducted with a radiolabeled capsule formulation. The results of excretion after oral and intravenous administration may differ.

Adverse Effects

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 drugs, the patient should use an additional method of birth control in order 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 and Aprepitant. It is also classified as Pregnancy Class B.

Drug Interactions

Patients should not be taking Neurokinin-1 (NK-1) receptor antagonists with the following prescription, nonprescription medications, as well as vitamins, herbal and nutritional supplements: Coumadin; antifungals such as ketoconazole and itraconazole; lansoprazole; clarithromycin (Biaxin); diltiazem; carbamazepine (Tegretol); HIV protease inhibitors, such as ritonavir (Norvir), and nelfinavir (Viracept); hormonal contraceptives; nefazodone; oral steroids such as dexamethasone and methylprednisolone; paroxetine; phenytoin; cancer chemotherapy medications such as docetaxel, etoposide, ifosfamide, imatinib (Gleevec), irinotecan, paclitaxel , tamoxifen, vinblastine, vincristine, and vinorelbine; rifampin; tolbutamide; and troleandomycin (TAO); benzodiazepines such as alprazolam (Xanax), diazepam (Valium), midazolam (Versed), and triazolam (Halcion).

Contraindications

Patients taking pimozide should not take Neurokinin-1 (NK-1) receptor antagonists. Inhibition of CYP3A4 enzyme by Neurokinin-1 (NK-1) receptor antagonists, such as, 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 QT prolongation. QT prolongation is a known adverse reaction of Pimozide. Neurokinin-1 (NK-1) receptor antagonists and Aprepitant are also contraindicated with the following drugs: 

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

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 drugs, the patient should use an additional method of birth control in order 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 and Aprepitant. It is also classified as Pregnancy Class B.

Monitoring

Central Nervous System Effects: There is no known monitoring requirement for Neurokinin-1 (NK-1) receptor antagonists.

Cardiovascular Effects: There is no known monitoring requirement for Neurokinin-1 (NK-1) receptor antagonists.

Respiratory Effects: There is no known monitoring requirement for Neurokinin-1 (NK-1) receptor antagonists.

Additional Monitoring Requirements/Precautions: There is no known additional monitoring requirement for Neurokinin-1 (NK-1) receptor antagonists.

Toxicity

Symptoms of an overdose of Neurokinin-1 (NK-1) receptor antagonists are drowsiness and headache. Aprepitant is associated with serum liver enzyme increases during therapy, but cases of clinically specific liver injury with jaundice have not been categorically linked.

Serum aminotransferase elevations during Neurokinin-1 (NK-1) receptor antagonists, Aprepitant therapy occurred in 6% of treated patients versus 4.3% in controls receiving cancer chemotherapy. The aminotransferase elevations were found to transient, mild to moderate in severity in some cases, and may not be associated with symptoms or jaundice. No convincing cases of clinically significant liver injury attributable to Neurokinin-1 (NK-1) receptor antagonists and Aprepitant have been published in the literature. Therefore, significant liver injury from Neurokinin-1 (NK-1) receptor antagonists, Aprepitant, or Fosaprepitant will be exceeding rare.