Indications
Aprepitant is primarily indicated for the prevention of nausea and vomiting in patients undergoing highly emetogenic cancer chemotherapy, particularly when high-dose cisplatin is administered. It is typically used in combination with other antiemetic agents to enhance its efficacy in managing these acute and delayed symptoms.
Pharmacodynamics
As an antiemetic, aprepitant functions as a substance P/neurokinin 1 (NK1) receptor antagonist. It offers a targeted approach for the prevention of nausea and vomiting associated with initial and subsequent courses of highly emetogenic chemotherapy. Aprepitant exhibits a selective high-affinity binding to human NK1 receptors and demonstrates negligible affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, which are common targets in existing chemotherapy-induced nausea and vomiting therapies.
Absorption
Aprepitant is characterized by a mean absolute oral bioavailability ranging from 60% to 65%. This indicates a moderate level of absorption when administered orally, facilitating its effective use in oral dosage forms for patients.
Metabolism
The metabolism of aprepitant is predominantly mediated by CYP3A4 enzymes, with minor contributions from CYP1A2 and CYP2C19. In human plasma, approximately seven metabolites have been identified, each exhibiting minimal pharmacological activity, reflecting the complex metabolic pathway and biotransformation of aprepitant in the body.
Mechanism of Action
Aprepitant functions through a central mechanism to effectively inhibit emesis, as demonstrated in animal studies with emetogenic chemotherapeutic agents like cisplatin. Both animal and human Positron Emission Tomography (PET) studies confirm that Aprepitant crosses the blood-brain barrier and binds to NK1 receptors in the brain. Additionally, research indicates that Aprepitant enhances the antiemetic properties of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone. It is effective in suppressing both the acute and delayed phases of cisplatin-induced emesis.
