Aprepitant (and Fosaprepitant)

Mechanism

Mechanism of action

Substance P is a peptide from the tachykinin family that acts synergistically in the central nervous system, being located in high concentrations in the nucleus of the solitary tract and in the area postrema of the gastric chemoreceptor trigger zone. It behaves as the main mediating neurotransmitter in the phase of late emesis induced by highly emetogenic chemotherapy (such as cisplatin).

Aprepitant is a selective, competitive, high-affinity antagonist for NK₁ receptors. By persistently and specifically occupying the binding site of the central NK₁ receptor, it blocks the action of endogenous substance P, neutralizing in a coordinated manner the activation of gastric bulbar vomiting centers induced by delayed-acting chemotherapy drugs.

Fosaprepitant: The Water-soluble Prodrug

Fosaprepitant is a highly water-soluble phosphate ester of aprepitant specifically formulated for intravenous administration. After injection, it is rapidly transformed by phosphatases intravascularly into free active aprepitant in less than 30 minutes. 115 mg of fosaprepitant is exactly molar equivalent to 100 mg of oral aprepitant.

Pharmacokinetics

Pharmacokinetics

• Absorption: Good oral absorption but with variable bioavailability (≈ 60% - 65%). It is not significantly altered by the concomitant administration of food.
• Distribution: Average volume of distribution of 70 L. Highly lipophilic. It extensively crosses the human blood-brain barrier to bind to brain NK₁ receptors. Binding to plasma proteins greater than 95%, with special affinity for albumin.
• Metabolism: Extensive hepatic oxidation via the microsomal system, predominantly mediated by CYP3A4, with minor contributions from CYP1A2 and CYP2C19. The resulting metabolites are biologically inactive.
• Excretion: It is not eliminated unchanged through the kidneys. Less than 5% is recovered in the urine. Its elimination is mixed fecal and biliary as conjugated inactive metabolites.
• Half-life: 9 to 13 hours. Allows a single daily administration.

Indicators and dose

Approved indications

• Prevention of nausea and vomiting associated with repeated cycles of highly emetogenic oncological chemotherapy (including regimens based on high doses of cisplatin).
• Prevention of nausea and vomiting associated with moderately emetogenic chemotherapy, administered in combination with a 5-HT₃ receptor antagonist (such as ondansetron) and a corticosteroid (dexamethasone) synergistically.

Dosage and Clinical Adjustment

Adults (Standard 3-day regimen combined with ondansetron and dexamethasone):

• Day 1: 125 mg orally one hour before chemotherapy treatment.
• Days 2 and 3: 80 mg orally in the morning on an empty stomach.
• Intravenous alternative (Fosaprepitant): 150 mg intravenously as a rapid infusion over 20-30 minutes administered only on day 1 of the treatment cycle.

Adjustments in Insufficiencies: No dose adjustments are required in patients with mild to moderate renal or hepatic insufficiency. Close caution in hepatic insufficiency Child-Pugh C.

Security

Contraindications

• Absolute: Known hypersensitivity to aprepitant, fosaprepitant or components of the formulation. Coadministration with drugs that are substrates of CYP3A4 and that have a narrow therapeutic margin such as pimozide, terfenadine, astemizole or cisapride (the metabolic blockade induced by aprepitant can trigger serious ventricular arrhythmias associated with overdose of these compounds).
• Relative: Child-Pugh C liver disease (severe liver failure) due to the paucity of large-scale controlled kinetic data.

Adverse effects (ADRs)

• Frequent (>1/100): Extreme fatigue (asthenia), headache, dizziness, persistent hiccups (due to inhibition of NK₁ receptors of the phrenic nerves), mild constipation, transient increase in hepatic transaminases, marked decrease in appetite.
• Infrequent / Rare: Dermal allergic hypersensitivity reactions, mild neutropenia. Local reactions at the intravenous infusion site (pain, erythema, phlebitis due to fosaprepitant).

Drug interactions

• Interaction with Dexamethasone and Methylprednisolone: Aprepitant is a moderate and time-dependent inhibitor of the liver enzyme CYP3A4. As dexamethasone is metabolized by this route, coadministration with aprepitant doubles the area under the curve (AUC) of the corticosteroid. Mandatory adjustment: The dose of oral dexamethasone should be reduced by 50% systematically when administered with aprepitant.
• Interaction with Oral Contraceptives: Aprepitant induces CYP3A4 activity late. Co-administered with birth control pills containing ethinyl estradiol and norethisterone, it drastically reduces their contraceptive effectiveness. Women should use barrier methods during treatment and for 28 days after the last dose of aprepitant.
• Interaction with Warfarin: Transient induction of warfarin metabolism mediated by CYP2C9. It can cause significant reductions in prothrombin time (INR). The INR should be closely monitored in the 7-10 days after the start of each therapeutic cycle.