Aprepitant is an oral medication used to prevent nausea and vomiting caused by chemotherapy, especially highly emetogenic chemotherapy (HEC) regimens, and to prevent postoperative nausea and vomiting (PONV). It works by selectively inhibiting the substance P/neurokinin 1 (NK1) receptor, which is involved in the vomiting reflex. By blocking this receptor, aprepitant reduces the activity of the brain’s vomiting center, thus preventing nausea and vomiting.

1. Mechanism of Action

Aprepitant is a selective antagonist of the neurokinin 1 (NK1) receptor. Substance P, a neuropeptide involved in the vomiting reflex, binds to the NK1 receptor in the brain, particularly in the area postrema, which triggers nausea and vomiting. Aprepitant blocks this receptor, preventing substance P from binding and activating the vomiting pathway. It is typically used in combination with other antiemetics (e.g., 5-HT3 antagonists and corticosteroids) for synergistic effects.

2. Indications

• Chemotherapy-induced nausea and vomiting (CINV): Aprepitant is used in combination with other medications (such as 5-HT3 antagonists and corticosteroids) to prevent acute and delayed nausea and vomiting caused by highly or moderately emetogenic chemotherapy regimens.
• Postoperative nausea and vomiting (PONV): Used for the prevention of nausea and vomiting following surgery.

3. Dosage and Administration

• Chemotherapy-Induced Nausea and Vomiting:
  • Initial Dose: 125 mg orally 1 hour before the start of chemotherapy on Day 1.
  • Subsequent Doses: 80 mg orally once daily on Days 2 and 3.
  • Aprepitant is typically used in combination with a 5-HT3 antagonist (such as ondansetron) and dexamethasone for optimal efficacy.
• Postoperative Nausea and Vomiting:
  • Dose: 40 mg orally, administered 1 hour before anesthesia induction.
• Special Populations:
  • Renal Impairment: No dose adjustment is required for patients with renal impairment.
  • Hepatic Impairment: Aprepitant should be used cautiously in patients with hepatic impairment, and the dose may need adjustment based on the severity of liver dysfunction.

4. Contraindications

• Hypersensitivity to aprepitant or any component of the formulation.
• Drug Interactions: Aprepitant is known to interact with several drugs, including certain CYP3A4 substrates (e.g., warfarin, oral contraceptives, corticosteroids), and should not be co-administered with drugs that are contraindicated in CYP3A4 inhibition.

5. Warnings and Precautions

• Drug Interactions: Aprepitant is a strong inhibitor of the CYP3A4 enzyme, which metabolizes a variety of drugs. Co-administration with drugs metabolized by this enzyme can lead to increased plasma levels of those drugs, potentially causing toxicity.
  • CYP3A4 Substrates: Adjust the dose of drugs that are CYP3A4 substrates (e.g., warfarin, benzodiazepines, corticosteroids).
  • Hormonal Contraceptives: Aprepitant can reduce the effectiveness of hormonal contraceptives. Additional non-hormonal birth control methods should be used during and for up to 28 days after treatment.
• Hepatic Impairment: Caution is advised in patients with hepatic impairment. A reduced dose may be required in patients with moderate to severe hepatic impairment.
• Pediatric Use: The safety and effectiveness of aprepitant in children under 6 months of age have not been established.

6. Side Effects

• Common:
  • Fatigue
  • Dizziness
  • Diarrhea
  • Hiccups
  • Headache
• Serious:
  • Severe allergic reactions (e.g., anaphylaxis, rash, swelling, difficulty breathing).
  • Liver enzyme abnormalities: Elevated liver function tests may occur in some patients.
  • Drug interactions leading to toxicity: Significant interactions with other medications due to its effect on CYP3A4 enzymes.
  • Fertility and pregnancy: Though not teratogenic in animal studies, aprepitant should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

7. Drug Interactions

• CYP3A4 Substrates: Aprepitant inhibits CYP3A4, which can lead to increased plasma levels of drugs metabolized by this enzyme (e.g., cyclosporine, midazolam, atorvastatin, warfarin).
• CYP2C9 Substrates: Aprepitant can also induce CYP2C9, affecting drugs metabolized by this enzyme (e.g., warfarin).
• Steroids (Dexamethasone): Aprepitant can increase the plasma concentrations of dexamethasone; therefore, doses of corticosteroids may need to be reduced when used concurrently with aprepitant.

8. Pharmacokinetics

• Absorption: Aprepitant is well absorbed following oral administration, with peak plasma concentrations occurring approximately 4 hours after administration.
• Distribution: Aprepitant has a large volume of distribution and is highly protein-bound (approximately 95%).
• Metabolism: It is extensively metabolized in the liver by CYP3A4 enzymes.
• Excretion: The drug is eliminated primarily via feces (about 90%) and to a lesser extent via urine. The half-life is approximately 9 to 13 hours.

9. Storage

• Store at room temperature, away from moisture and heat (25°C or 77°F).
• Keep the medication in its original packaging and protect it from light.