NK1 Receptor Antagonist Antiemetics

NK1 receptor antagonists block substance P in the brainstem and give the strongest protection against delayed chemotherapy-induced vomiting. They are used with a 5HT3 antagonist and dexamethasone for highly emetogenic regimens.

Pharmacokinetics. Aprepitant is metabolised by CYP3A4. It is a moderate CYP3A4 inhibitor and induces CYP2C9. Rolapitant has a half life of about 7 days.

• Aprepitant 125 mg orally on day 1, then 80 mg on days 2 and 3.
• Fosaprepitant 150 mg intravenously once on day 1.
• Netupitant 300 mg with palonosetron 0.5 mg orally once on day 1.
• Rolapitant 180 mg orally once.

Differences. Fosaprepitant is the intravenous prodrug of aprepitant. Fixed combinations simplify dosing.

• Highly emetogenic chemotherapy (cisplatin, anthracycline with cyclophosphamide): add an NK1 antagonist to a 5HT3 antagonist and dexamethasone.
• Moderately emetogenic chemotherapy with risk factors: consider addition.
• Dexamethasone dose is reduced by about half with aprepitant, for example 12 mg on day 1 and 8 mg on days 2 to 4.

Selection. Not first-line for postoperative or general nausea. Cost and availability limit use in many East African centres.

Contraindications. Pimozide, cisapride.

Adverse effects. Fatigue, hiccups, constipation, headache, infusion site reactions (fosaprepitant), hypersensitivity.

Interactions.

• Warfarin: INR may fall; check 7 to 10 days after each cycle.
• Hormonal contraceptives: reduced effect; use a backup method during treatment and for 1 month after.
• Rifampicin, phenytoin and carbamazepine lower aprepitant levels; avoid.
• Ketoconazole, clarithromycin and ritonavir raise levels.
• Raises dexamethasone, midazolam and some chemotherapy drug levels.

Special groups.

• Liver impairment: no adjustment in mild to moderate; limited data in severe.
• Kidney impairment: no adjustment.
• Pregnancy and breastfeeding: limited data; use only when benefit is clear.
• Children: weight-based doses from 6 months are licensed; specialist use.

Monitoring. INR, hepatic enzymes and hypersensitivity.

Referral and escalation. Specialist oncology direction for regimen selection.