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Show detailsContinuing Education Activity
Neurokinin-1 (NK-1) receptor antagonists are antiemetic drugs with unique anxiolytic, antidepressant, and antiemetic properties. The discovery of NK-1 receptor blockers was crucial in preventing emesis associated with cancer chemotherapy. The NK-1 receptor antagonist competitively binds to the NK-1 receptor, thereby blocking the binding of substance P and preventing the transmission of the emetic signal. This activity reviews the indications, contraindications, mechanism of action, adverse event profile, and other crucial aspects of antiemetic NK-1 receptor blockers within the clinical setting. This activity also focuses on essential information required by members of an interprofessional team responsible for treating patients who stand to benefit therapeutically from these agents.
Objectives:
- Identify appropriate candidates for neurokinin-1 receptor antagonists based on their understanding of the patient's chemotherapy regimen and emetogenic risk.
- Apply knowledge of neurokinin-1 receptor antagonists in diverse clinical scenarios, tailoring treatment approaches to individual patient needs and characteristics.
- Select the most appropriate neurokinin-1 receptor antagonist based on patient-specific factors, treatment goals, and potential drug interactions.
- Collaborate with other interprofessional healthcare teams, such as pharmacists and nurses, optimizing the use of neurokinin-1 receptor antagonists to achieve the best outcomes in managing chemotherapy-induced nausea and vomiting.
Indications
Neurokinin-1 (NK-1) receptor antagonists constitute a category of antiemetic medications with distinct anxiolytic, antidepressant, and antiemetic properties. The discovery of NK-1 receptor blockers was crucial in preventing emesis associated with cancer chemotherapy.[1][2]
The NK-1 receptor inhibitor class is 1 of the 7 drug classes used to suppress nausea and vomiting in patients undergoing cancer chemotherapy. The other classes of antiemetic drugs include serotonin (5-hydroxytryptamine or 5-HT) receptor antagonists, dopamine (D) receptor antagonists, histamine (H) receptor antagonists, NK-1 antagonists, antimuscarinic agents, cannabinoids, and corticosteroids. Patients may experience nausea, vomiting, and vertigo in various situations, such as during pregnancy, cancer chemotherapy, and motion sickness while traveling in a car, boat, or cruise ship. Examples of NK-1 receptor inhibitors include aprepitant, rolapitant, casopitant, netupitant, maropitant, and fosaprepitant. Rolapitant, a recently developed highly selective NK-1 receptor antagonist, boasts an exceptionally extended plasma half-life (T1/2) of 180 hours. Notably, it obtained approval from the U.S. Food and Drug Administration (FDA) in September 2015 to prevent delayed emesis induced by chemotherapy.[3]
FDA-Approved Indications
NK-1 receptor antagonists can effectively treat postsurgical nausea and vomiting as well as nausea and vomiting induced by cancer chemotherapy. Fosaprepitant is administered intravenously (IV) and undergoes conversion to aprepitant within 30 minutes after infusion. Aprepitant is available for both oral and IV administration in various strengths and is approved for the treatment of both chemotherapy-related and postoperative nausea and vomiting. The oral formulation of netupitant, combined with palonosetron, has been approved. Casopitant is currently under investigation and in the developmental stage. On the other hand, maropitant is an antiemetic used in dogs and cats in the United States.
Off-Label Uses
Currently, no off-label uses for NK-1 receptor antagonists are reported.
Mechanism of Action
NK-1 receptor antagonists exhibit anti-nausea and anti-vomiting properties by acting through 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 belongs to a class of neuropeptides known as neurokinins and is an excitatory neurotransmitter with a significant role in pain perception. NK-1—the receptor of substance P—is a G protein–coupled receptor consisting of 7 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, available in both oral and IV formulations, are highly selective in crossing the blood-brain barrier to occupy NK-1 receptors in the brain. Animal and human positron emission tomography (PET) studies have shown that NK-1 receptor antagonists can cross the blood-brain barrier and bind to brain NK-1 receptors. Notably, aprepitant exhibits no affinity for corticosteroid, serotonin, or dopamine receptors.[4][5]
Nausea and vomiting associated with emetogenic chemotherapy have 2 components: a universally acute phase occurring within 24 hours after chemotherapy and a delayed phase that impacts only certain patients between days 2 and 5. Serotonin (5-HT3) receptor antagonists exhibit limited effectiveness against delayed emesis. However, targeting the receptors for the neuropeptide substance P, including aprepitant (and its parenteral formulation fosaprepitant), NK-1 receptor inhibitors demonstrate antiemetic effects by preventing delayed nausea. They also enhance the effectiveness of standard antiemetic regimens in patients undergoing multiple cycles of chemotherapy.[6][7]
Pharmacokinetics
The drug aprepitant will serve as the representative of its class, although individual agents may vary.[8]
Absorption: In the fasting state, following a single oral dose of 40 mg aprepitant, the mean area under the plasma concentration-time curve (AUC0-∞) is determined to be 7.8 mcg x h/mL, and the mean peak plasma concentration (Cmax) is 0.7 mcg/mL, observed at around 3 hours after administration (Tmax). The onset of action for oral aprepitant is 1 hour, with the peak blood concentration reached at 4 hours.
After a single 125 mg oral dosage of aprepitant on day 1 and 80 mg once daily on days 2 and 3, the area under the curve (AUC) for 0 to 24 hours is measured to be 19.6 mcg x h/mL on day 1 and 21.2 mcg x h/mL on day 3, respectively. A 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. The onset of action for oral aprepitant is 1 hour, and the peak blood concentration is 4 hours, as published in the manufacturer's package insert. Aprepitant's pharmacokinetics are non-linear across the clinical dose range.
Distribution: Aprepitant has a volume of distribution of 70 L. The mean absolute oral bioavailability of aprepitant is approximately 60% to 65%.[9] Protein binding of aprepitant exceeds 95%.
Metabolism: NK-1 receptor antagonists, such as aprepitant, undergo primary metabolism primarily by cytochrome P450 enzymes, notably CYP3A4, with minor contributions from CYP1A2 and CYP2C19. Researchers have identified 7 less active metabolites of aprepitant in human plasma.[10] The manufacturer's package insert and other publications indicate that the duration of action of aprepitant is 24 hours. The biological half-life of aprepitant falls within the range of 9 to 13 hours. Following the pharmacokinetic principle, it is expected to take approximately 4 to 5 half-lives (T1/2) to eliminate most of the absorbed drug from the body. Consequently, clinicians should anticipate the duration of action of aprepitant to be at least 40 hours.
Elimination: The apparent plasma clearance of aprepitant ranges from 62 to 90 mL/min.[9] After a single administration of an IV 100 mg dose of radiolabeled [14C]-aprepitant in healthy subjects, 45% of the radioactivity was recoverable in feces, and 57% was excreted in the urine. No study was conducted with a radiolabeled capsule formulation. Therefore, the excretion results may differ after oral and IV administration.
Administration
Available Dosage Forms and Strengths
Aprepitant: This drug is offered in 40 mg, 80 mg, and 125 mg capsules. For adult dosing, it is recommended to administer 125 mg orally on chemotherapy day 1, followed by 80 mg on days 2 and 3. In addition, aprepitant is available in injection form, with a recommended dose of 32 mg IV as a single dose, initiated before anesthesia induction.
Rolapitant: This drug is available in 90 mg tablets, and the recommended dosage is 180 mg orally as a single dose, administered 2 hours before emetogenic chemotherapy.
Netupitant/palonostron: These drugs are available as 300 mg/0.5 mg capsules, dosed as 1 capsule 1 hour before chemotherapy, along with a corticosteroid.
Fosaprepitant: This drug comes in an injectable form, and the recommended dosage is 150 mg on day 1 of chemotherapy, administered 30 minutes before initiation. Fosaprepitant can be concurrently administered with a corticosteroid and a 5-HT3 antagonist.
Aprepitant is often administered with a 5-HT3 antagonist, such as ondansetron and a glucocorticoid.[9]
Specific Patient Populations
Hepatic impairment: The dosage adjustments and recommendations for drugs in patients with hepatic impairment are listed below.
- Aprepitant: Aprepitant does not require any dosage adjustment for patients belonging to Child-Hugh class A or B. However, the dosage adjustment for patients belonging to Child-Hugh class C is undefined.
- Rolapitant: Rolapitant does not require any dosage adjustment for patients belonging to Child-Hugh class A or B. However, the dosage adjustment for patients belonging to Child-Hugh class C is undefined.
- Netupitant/palonosetron: Netupitant/palonosetron is not recommended for patients belonging to Child-Hugh class C. Therefore, this medication should be avoided in such cases.
- Fosaprepitant: Fosaprepitant does not require any dosage adjustment for patients belonging to Child-Hugh class A or B. However, the dosage adjustment for patients belonging to Child-Hugh class C is undefined.[11]
Renal impairment: The dosage adjustments and recommendations for drugs in patients with renal impairment are listed below.
- Aprepitant: Aprepitant does not require dosage adjustment for hemodialysis patients, but its use in peritoneal dialysis is unclear.
- Rolapitant: No dosage adjustment is necessary for patients with creatinine clearance (CrCl) >30. Dosing is undefined for patients with CrCl <30 and for patients receiving hepatic or peritoneal dialysis.
- Netupitant/palonosetron: No dosage adjustment is required for patients with CrCl >30. Dosing is undefined for patients with CrCl <30 or those undergoing hepatic or peritoneal dialysis.
- Fosaprepitant: Fosaprepitant does not require dosage adjustment for hemodialysis patients, while its usage in peritoneal dialysis is undefined.
Pregnancy considerations: When contemplating the use of antiemetic medications during pregnancy, careful consideration is imperative.
- Aprepitant: Although data from human studies on the effects of aprepitant during pregnancy are unavailable, clinicians should carefully weigh the risks and benefits of this medication during pregnancy. Females of reproductive age who are undergoing treatment with aprepitant should use effective non-hormonal contraception to avoid pregnancy. In addition, it is also recommended to continue using contraception for at least 1 month after discontinuing the treatment, as aprepitant may reduce the effectiveness of hormonal contraceptives.[12]
- Rolapitant: Although data from human studies are unavailable, there is no known risk of teratogenicity based on data from animal studies.
- Netupitant/palonosetron: Based on data from animal studies, netupitant may have teratogenic risks. As for palonosetron, data from human studies are conflicting with the data obtained from ondansetron. Hence, the drug should be used with extreme caution, especially during the first trimester.
- Fosaprepitant: Data from human studies are unavailable for fosaprepitant. However, based on data from animal studies, risks regarding the teratogenicity of fosaprepitant are unknown.
Breastfeeding considerations: Data from human studies are unavailable to evaluate the risk of infant harm or the impact of NK-1 receptor antagonists on maternal milk production.
Pediatric patients: Rolapitant and netupitant are not approved for use in pediatric patients. For pediatric dosing of aprepitant and fosaprepitant, facility protocols or the package insert should be referred.
Older patients: No dosage adjustments for these drugs are recommended for older patients except for adjustments based on hepatic and renal considerations, as outlined above.
Adverse Effects
Adverse Reactions Associated With Antiemetic Drugs
The adverse reactions mentioned below are considered common effects of a particular class of medication unless otherwise specified.
Severe adverse reactions: Severe adverse reactions, including hives and rash, Stevens-Johnson syndrome (associated with aprepitant and fosaprepitant), angioedema, neutropenia, QT prolongation (specific to netupitant/palonosetron), and serotonin syndrome (specific to netupitant/palonosetron), have been reported.
Mild adverse reactions: Mild adverse reactions may include sleepiness, diarrhea, weakness, constipation, stomach pain, heartburn, nausea, hiccups, loss of appetite, headache, fever, itching, and hair loss.
Drug-Drug Interactions
Potential drug interactions may arise with NK-1 receptor antagonists due to changes in drug metabolism, specifically CYP3A4 inhibition. This can occur in patients concurrently using prescription and non-prescription medications, as well as herbal and nutritional supplements, and is considered a class effect.[13] Due to CYP3A4 inhibition, patients using pimozide should avoid NK-1 receptor antagonists. Inhibiting the CYP3A4 enzyme may increase plasma concentrations of pimozide—a CYP3A4 substrate. The drug interaction between pimozide and aprepitant could result in severe or life-threatening reactions, including QTc prolongation, a known adverse reaction of pimozide.[14]
The partial list of potential drug interactions that are either contraindicated or, at the very least, necessitate rigorous monitoring when coadministered with various NK-1 inhibitors include cisapride, colchicine, eliglustat, flibanserin, lomitapide, lonafarnib, pimozide, and thioridazine.
Netupitant/palonosetron is contraindicated with medications, including apomorphine, cisapride, dronedarone, eliglustat, flibanserin, levoketoconazole, lomitapide, lonafarnib, pimozide, and thioridazine.
During treatment with NK-1 receptor antagonists, female patients using birth control medication should use an additional non-hormonal method of contraception to prevent unplanned or unwanted pregnancy, as NK-1 receptor antagonists may diminish the effectiveness of oral contraceptives.[12] Furthermore, patients should maintain other pregnancy protection measures for 1 month after discontinuing NK-1 receptor antagonist therapy. Due to the extensive list of interacting drugs for NK-1 inhibitors, thorough medication reconciliation is essential for each patient.[9][15]
Contraindications
Contraindications to using NK-1 receptor antagonists include hypersensitivity to the drug or formulation ingredients. Specific agents are contraindicated in hepatic impairment, specifically in individuals classified as Child-Pugh class C.[16] The alcohol-containing injectable formulation of aprepitant is contraindicated in pregnancy.[3]
Monitoring
There are no established monitoring requirements or specific tests for NK-1 receptor antagonists concerning the central nervous, cardiovascular, respiratory, or other systems.
Toxicity
Symptoms of an overdose of NK-1 receptor antagonists may include drowsiness and headache. Although aprepitant is associated with increased serum liver enzyme during therapy, a verified correlation between clinically specific liver injury cases and jaundice has not been established.
Serum aminotransferase elevations during aprepitant therapy were observed in 6% of treated patients compared to 4.3% of controls receiving cancer chemotherapy. These elevations were generally mild to moderate, transient, and, in some cases, asymptomatic without jaundice. Published cases of clinically significant liver injury attributable to aprepitant are not convincingly documented in the literature. As a result, significant liver injury from aprepitant or fosaprepitant would be exceedingly rare.[10]
Enhancing Healthcare Team Outcomes
NK-1 receptor antagonists prove highly effective in managing nausea and vomiting induced by various factors. Despite their safety and efficacy, these drugs are prohibitively expensive and only used in hospital settings. Hospital pharmacists frequently receive alerts when physicians prescribe these drugs, prompting the ordering clinician to request a more cost-effective yet equally efficacious alternative.[17][18] To mitigate the impact on healthcare expenses, a committee comprising physicians, advanced practice practitioners, pharmacists, and hospital administrators should collaborate to formulate practice guidelines for utilizing these medications in hospital settings. The elevated cost of these drugs frequently renders them financially inaccessible for many patient populations, necessitating the implementation of special programs.[19]
To achieve therapeutic coherence, the interprofessional healthcare team must be in sync and work together toward a common goal. Given the significant drug interactions associated with NK-1 receptor antagonists, it is imperative for pharmacists to engage in communication with the ordering clinician whenever potential drug interactions could impact the effectiveness of the patient's therapeutic regimen, as mentioned above. Similarly, nursing staff should be well-informed about proper drug administration and can consult with the pharmacist or physician regarding any concerns. Nurses are in an ideal position to monitor the effectiveness of treatments and identify any adverse reactions. They should promptly report any issues to the clinician who ordered the treatment.
NK-1 receptor antagonists can be essential for oncologists, oncology-specialized nurses, and pharmacists in addressing chemotherapy-related nausea. These instances underscore the importance of adopting an interprofessional team approach to NK-1 receptor antagonist therapy, ensuring the delivery of maximum therapeutic efficacy while minimizing adverse events and drug interactions.
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Disclosure: Michael Ibrahim declares no relevant financial relationships with ineligible companies.
Disclosure: Mark Pellegrini declares no relevant financial relationships with ineligible companies.
Disclosure: Charles Preuss declares no relevant financial relationships with ineligible companies.
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- Antiemetic Neurokinin-1 Receptor Blockers - StatPearlsAntiemetic Neurokinin-1 Receptor Blockers - StatPearls
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