NK1 receptor antagonists

I. Introduction

Neurokinin-1 (NK1) receptor antagonists are a class of pharmacologic agents that selectively inhibit the NK1 receptor, the primary receptor for substance P—a neuropeptide involved in emesis, pain transmission, stress response, inflammation, and mood regulation. NK1 receptor antagonists are most prominently used in the prevention of chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV). More recently, this class has also been explored for applications in psychiatric disorders, chronic pruritus, and neuropathic pain.

The most established use remains in supportive care in oncology, where NK1 receptor antagonists are part of guideline-recommended antiemetic regimens, particularly for patients receiving highly emetogenic chemotherapy (HEC).

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II. NK1 Receptors and Substance P: Physiological Role

• The NK1 receptor is a G protein-coupled receptor (GPCR) predominantly found in the central nervous system, gastrointestinal tract, and vascular endothelium.

• Its natural ligand, substance P, is part of the tachykinin family of neuropeptides.

• Upon binding, substance P stimulates NK1 receptors to:

  • Mediate vomiting via the brainstem vomiting center and nucleus tractus solitarius

  • Participate in nociception and neurogenic inflammation

  • Influence mood regulation and stress-related behavior

  • Promote vasodilation, bronchoconstriction, and cell proliferation

By blocking NK1 receptors, these antagonists prevent substance P from exerting its effects—particularly in the emetic pathway.

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III. Mechanism of Action

NK1 receptor antagonists:

• Bind with high affinity and selectivity to the NK1 receptor, thereby blocking substance P from activating the receptor.

• Inhibit emesis in both acute and delayed phases by acting centrally (brainstem vomiting center and area postrema).

• Work synergistically with 5-HT3 antagonists and corticosteroids, making them essential in multi-drug antiemetic regimens.

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IV. Approved NK1 Receptor Antagonists

Generic Name	Brand Name(s)	Formulation	Indication(s)
Aprepitant	Emend®, Cinvanti®	Oral (capsule), IV	CINV, PONV
Fosaprepitant	Emend IV®	IV prodrug	CINV
Netupitant	In Akynzeo® combo	Oral (with palonosetron)	CINV
Rolapitant	Varubi®	Oral (also IV in some regions)	CINV
Tradipitant	Experimental	Oral	Pruritus, motion sickness (under study)
Orvepitant, Vestipitant, Casopitant	Investigational	Oral	Depression, anxiety, and sleep disorders

V. Pharmacokinetics and Dosing

Drug	Half-life	Onset of Action	Duration	Metabolism	Dosing Frequency
Aprepitant	~9–13 hours	~4 hours	>24 h	CYP3A4 (substrate/inhibitor)	Once daily (1–3 days)
Fosaprepitant	Prodrug of aprepitant	Rapid	Same as aprepitant	Rapid conversion to aprepitant	Single IV dose
Rolapitant	~180 hours	1–8 hours	Several days	CYP2D6 (substrate), does not inhibit CYP3A4	Single dose
Netupitant	~80 hours	~2 hours	Long	CYP3A4 (substrate/inhibitor)	Single dose
Tradipitant	~8 hours (est.)	Under research	Short to moderate	Under investigation	Not approved

VI. Clinical Indications

A. Chemotherapy-Induced Nausea and Vomiting (CINV)

• Used in combination with a 5-HT3 antagonist and dexamethasone

• Particularly effective against delayed-phase CINV (24–120 hours post-chemotherapy)

• Used for both highly emetogenic (e.g., cisplatin) and moderately emetogenic chemotherapy

Examples of triple therapy regimens:

• Aprepitant + Ondansetron + Dexamethasone

• Akynzeo® (Netupitant + Palonosetron) + Dexamethasone

• Rolapitant + Granisetron + Dexamethasone

B. Postoperative Nausea and Vomiting (PONV)

• Aprepitant approved for PONV prophylaxis in high-risk surgical patients

• Given preoperatively (oral or IV)

C. Radiation-Induced Nausea and Vomiting

• Off-label use similar to CINV protocols

D. Investigational/Off-label Indications

• Chronic pruritus (tradipitant)

• Motion sickness

• Neuropathic pain

• Depression and anxiety disorders (via central substance P modulation)

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VII. Comparative Overview

Drug	Unique Features	Notes
Aprepitant	First-in-class oral NK1 antagonist	Oral route limits perioperative use
Fosaprepitant	IV prodrug with rapid conversion to aprepitant	Commonly used in inpatient settings
Netupitant	Combined with palonosetron in single capsule (Akynzeo)	Superior control of both acute and delayed CINV
Rolapitant	Longest half-life (~7 days)	Minimal CYP3A4 interaction – fewer interactions
Tradipitant	Under investigation for dermatologic and GI indications	Not FDA-approved yet

VIII. Adverse Effects and Safety Profile

NK1 receptor antagonists are generally well tolerated. Common adverse effects include:

A. Common Adverse Effects

• Fatigue

• Headache

• Hiccups

• Constipation or diarrhea

• Anorexia

B. Serious Adverse Reactions

• Hypersensitivity reactions (more with fosaprepitant IV)

• Elevated liver enzymes (rare)

• Infusion site reactions (especially with fosaprepitant)

• CYP3A4 inhibition-related drug interactions (esp. aprepitant, netupitant)

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IX. Drug Interactions

A. CYP450 Interactions

Agent	CYP3A4 Inhibition	CYP3A4 Substrate	CYP2D6 Inhibition
Aprepitant	Yes	Yes	Mild
Netupitant	Yes	Yes	No
Rolapitant	No	No	Yes (strong)

B. Interacting Medications

• Corticosteroids: May need dose adjustment (e.g., reduce dexamethasone when used with aprepitant)

• Oral contraceptives: Efficacy may be reduced—advise additional contraception

• Warfarin: INR monitoring advised (especially with aprepitant)

Rolapitant does not inhibit CYP3A4, making it safer for patients on multiple drugs metabolized by this pathway.

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X. Contraindications and Cautions

Contraindication	Description
Hypersensitivity	Especially to IV fosaprepitant
Concomitant use with pimozide	Due to increased pimozide levels → QT prolongation
Severe hepatic impairment	Use with caution; monitor LFTs
Pregnancy and lactation	Limited data; use only if clearly needed
Children	Approved for select agents (e.g., aprepitant ≥6 mos)

XI. Use in Special Populations

• Pregnancy Category B/C (varies by agent)

• Pediatrics: Aprepitant and fosaprepitant approved for use in children ≥6 months

• Renal impairment: No dose adjustment required

• Hepatic impairment: Caution advised in moderate-to-severe liver disease

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XII. Emerging and Investigational NK1 Antagonists

Agent	Status	Potential Indications
Tradipitant	Phase 3	Pruritus in atopic dermatitis, motion sickness
Casopitant	Withdrawn; may be re-evaluated	CINV, PONV, depression
Orvepitant	Investigational	Depression, PTSD
Vestipitant	Early-stage	Sleep disorders, anxiety

These newer agents aim to exploit the broader CNS effects of NK1 receptor modulation beyond emesis.

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XIII. Guidelines and Recommendations

1. ASCO, NCCN, and MASCC Guidelines

• Recommends NK1 receptor antagonists for highly emetogenic chemotherapy (HEC) in combination with:

  • 5-HT3 receptor antagonist (e.g., ondansetron)

  • Dexamethasone

• Netupitant/palonosetron (Akynzeo®) and rolapitant are acceptable alternatives to aprepitant

2. ERAS (Enhanced Recovery After Surgery) Guidelines

• Include NK1 receptor antagonists (e.g., aprepitant) for PONV prophylaxis in high-risk patients

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XIV. Summary of Facts

• NK1 receptor antagonists block substance P, preventing activation of central emetic pathways

• Primarily used for CINV, especially delayed-phase emesis

• Aprepitant, netupitant, rolapitant are standard agents; tradipitant is investigational

• Often co-administered with 5-HT3 antagonists and corticosteroids

• Generally well tolerated; notable for CYP enzyme interactions

• Rolapitant is safest in polypharmacy due to lack of CYP3A4 inhibition

• Increasing interest in dermatological, psychiatric, and GI indications