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Aprepitant

Aprepitant: A Key Player in the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV)

Introduction

One of the most feared and debilitating side effects of chemotherapy is nausea and vomiting, collectively known as chemotherapy-induced nausea and vomiting (CINV). Despite the availability of standard antiemetic therapies like serotonin (5-HT3) antagonists and corticosteroids, a significant number of patients still suffer from refractory or delayed symptoms. This is where Aprepitant, a neurokinin-1 (NK1) receptor antagonist, plays a crucial role. Aprepitant has transformed the landscape of supportive cancer care by targeting a different biochemical pathway associated with emesis. Marketed under the brand name Emend, and as a component in combination therapies like Fosaprepitant and Netupitant-Palonosetron, Aprepitant has been shown to significantly reduce both acute and delayed CINV when used in combination with other antiemetics.

Understanding Chemotherapy-Induced Nausea and Vomiting (CINV)

CINV is broadly categorized into five types:

  1. Acute – Occurs within the first 24 hours after chemotherapy.

  2. Delayed – Occurs after 24 hours and can last several days.

  3. Anticipatory – Conditioned response due to previous episodes.

  4. Breakthrough – Occurs despite prophylactic treatment.

  5. Refractory – Persists across multiple chemotherapy cycles.

Delayed CINV, in particular, is difficult to control and severely impacts a patient’s quality of life, nutritional status, and willingness to continue chemotherapy. Addressing it requires a multi-modal approach that includes NK1 receptor antagonism—the domain of Aprepitant.

Aprepitant:

Aprepitant is a highly selective NK1 receptor antagonist that works by blocking the action of substance P, a neuropeptide associated with emetic signaling in the brain.

Basic Drug Information

  • Generic Name: Aprepitant

  • Brand Name: Emend

  • Class: Antiemetic, NK1 receptor antagonist

  • Formulations: Oral capsules (40 mg, 80 mg, 125 mg), oral suspension, IV (as Fosaprepitant)

  • First FDA Approval: 2003

Mechanism of Action

The vomiting center in the medulla oblongata receives input from:

  • The chemoreceptor trigger zone (CTZ)

  • The gastrointestinal tract

  • The vestibular system

  • Higher cortical centers

Substance P is released in the central nervous system and binds to neurokinin-1 (NK1) receptors, especially in the nucleus tractus solitarius and area postrema, triggering the emetic reflex.

Aprepitant competitively binds to NK1 receptors and blocks substance P, thereby:

  • Reducing acute CINV when used with 5-HT3 antagonists and corticosteroids

  • Significantly reducing delayed CINV, which 5-HT3 antagonists do not effectively manage alone

Pharmacokinetics and Metabolism

Property Value
Bioavailability ~60–65% (oral)
Protein Binding >95%
Peak Plasma Time ~4 hours
Half-life 9–13 hours
Metabolism CYP3A4 (major), CYP1A2, CYP2C19 (minor)
Excretion Feces (57%), Urine (45%)

Aprepitant’s long half-life allows for once-daily dosing, and its ability to cross the blood-brain barrier makes it ideal for central emetic control.

Clinical Indications

1. Chemotherapy-Induced Nausea and Vomiting (CINV)

  • Acute and delayed nausea and vomiting

  • Most effective when used as part of a triple regimen:

    • Day 1: Aprepitant + 5-HT3 antagonist (e.g., ondansetron) + dexamethasone

    • Days 2-3: Aprepitant + dexamethasone

2. Postoperative Nausea and Vomiting (PONV)

  • Sometimes used off-label or in specific cases of refractory PONV

  • Typically single-dose oral or IV administration

3. Off-Label Uses

  • Nausea in palliative care or opioid-induced vomiting

  • Cyclic vomiting syndrome

  • Cannabinoid hyperemesis syndrome (CHS)

  • Hyperemesis gravidarum (under investigation)

Formulations and Dosing

Oral Aprepitant (Emend)

  • Day 1: 125 mg 1 hour before chemotherapy

  • Days 2 & 3: 80 mg once daily

Fosaprepitant (IV Prodrug)

  • Administered as a single 150 mg IV dose on Day 1 (converted to aprepitant in plasma)

  • Used as a convenient alternative to multi-day oral regimens

Pediatric Use

  • Approved for children ≥6 months (oral) and ≥6 months (IV)

  • Weight-based dosing

Efficacy Data and Clinical Trials

1. Study 054 (Hesketh et al., NEJM 2003)

  • Showed superior control of both acute and delayed CINV with aprepitant regimen vs. standard therapy.

  • Complete response (no vomiting, no rescue meds):

    • Aprepitant arm: 72%

    • Standard arm: 52%

2. Multinational Trials

  • Consistent across different chemotherapy agents (cisplatin, carboplatin, anthracycline/cyclophosphamide regimens)

3. Pediatric Trials

  • Demonstrated safety and efficacy in reducing CINV in young patients receiving high-dose chemotherapy

Advantages of Aprepitant

1. Targeting Delayed CINV

  • Most antiemetics are ineffective beyond 24 hours

  • Aprepitant is essential for multi-day protection

2. Oral and IV Flexibility

  • Allows for tailored regimens based on patient preference or tolerability

3. Minimal Sedation

  • Unlike dopamine antagonists, does not cause drowsiness

4. Enhanced Quality of Life

  • Better nausea/vomiting control leads to:

    • Improved nutritional intake

    • Greater treatment compliance

    • Reduced hospital visits

Side Effects and Safety Profile

Aprepitant is generally well-tolerated. Common side effects include:

System Effects
GI Constipation, diarrhea, hiccups
CNS Fatigue, dizziness, headache
Hepatic Mild ALT/AST elevation (rare)
Allergy Hypersensitivity and infusion reactions (IV form)

Drug Interactions

Because aprepitant is a moderate CYP3A4 inhibitor, it may affect the metabolism of other drugs:

Drug Interaction
Dexamethasone ↑ Levels → dose reduction needed
Warfarin ↓ INR → monitor closely
Oral Contraceptives ↓ Efficacy → use backup method
Benzodiazepines ↑ Sedation
Chemotherapy (etoposide, vincristine) Monitor for toxicity, although usually safe

Contraindications and Cautions

  • Hypersensitivity to aprepitant or components

  • Caution in severe hepatic impairment

  • Not typically used during pregnancy unless clearly necessary (Category B)

  • Not first-line for patients with a history of severe depression or CNS disorders, though rare

Comparison with Other NK1 Receptor Antagonists

Drug Form Half-life Route Notes
Aprepitant Capsule/suspension 9–13 hrs Oral First-generation
Fosaprepitant Prodrug of Aprepitant - IV Single-day alternative
Netupitant (in Akynzeo) Combo with palonosetron 80 hrs Oral Once per cycle
Rolapitant Longest half-life 180 hrs Oral/IV CYP2D6 interactions

Aprepitant offers a good balance of efficacy, duration, and accessibility, making it ideal for most patients starting emetogenic chemotherapy.

Real-World Experience

Post-marketing surveillance and real-world studies have reaffirmed:

  • High adherence rates

  • Patient-reported outcomes showing better nausea control

  • Decreased reliance on rescue antiemetics

  • Enhanced appetite and well-being during chemotherapy

Hospitals often include aprepitant in standardized antiemetic order sets, especially for highly emetogenic chemotherapy (HEC).

Cost and Access

Though originally expensive, generic Aprepitant is now widely available and covered by most insurance plans. This has increased its use, particularly in developing countries where access to biologic antiemetics may be limited.

Programs offering patient assistance and inclusion in oncology care bundles further promote its use.

Future Directions

1. Extended Applications

  • Trials ongoing in functional GI disorders, palliative care, and migraine-associated nausea

2. Improved Formulations

  • Orally disintegrating tablets (ODTs) and transdermal patches under development

  • Subcutaneous options for home care

3. Combination Therapies

  • Enhanced protocols using NK1s, 5-HT3 antagonists, and olanzapine are being evaluated for multimodal emetic prevention

Conclusion

Aprepitant has been a game-changer in the management of chemotherapy-induced nausea and vomiting. By targeting the NK1 receptor pathway, it provides essential protection against both acute and delayed emesis, improving the tolerability and success of cancer treatments. With expanding roles in supportive and palliative care, newer formulations, and combination regimens, Aprepitant continues to be an invaluable part of modern oncology care.