aprepitant + fosaprepitant

Aprepitant and fosaprepitant are antiemetic medications used primarily to prevent chemotherapy-induced nausea and vomiting (CINV). Fosaprepitant is a prodrug of aprepitant, meaning it's converted to aprepitant in the body. They work by blocking neurokinin-1 (NK1) receptors, which are involved in the vomiting reflex. **Identification** Aprepitant and fosaprepitant are selective high-affinity antagonists of human substance P/neurokinin 1 (NK1) receptors. Fosaprepitant is administered intravenously and rapidly converts to aprepitant in the body, while aprepitant is given orally. Both drugs have little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, which are targets of other antiemetic therapies. **Clinical Use** These medications are indicated for: - Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin - Prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy (MEC) They are typically used in combination with other antiemetic agents, such as 5-HT3 receptor antagonists (like ondansetron) and corticosteroids (like dexamethasone), to provide comprehensive control of CINV. **Mechanism of Action** Fosaprepitant is a prodrug that is rapidly converted to aprepitant by phosphatase enzymes when administered intravenously. Aprepitant works by: - Selectively antagonizing NK1 receptors in the brain - Crossing the blood-brain barrier to occupy brain NK1 receptors - Inhibiting emesis induced by cytotoxic chemotherapeutic agents like cisplatin via central actions - Augmenting the antiemetic activity of 5-HT3 receptor antagonists and corticosteroids. This mechanism complements traditional antiemetic drugs, enhancing overall control of CINV. **Pharmacokinetics** - **Bioequivalence**: Fosaprepitant has been demonstrated to be bioequivalent to aprepitant. - **Conversion**: Fosaprepitant is rapidly converted to aprepitant within 30 minutes following the end of infusion. - **Metabolism**: Aprepitant is primarily metabolized by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. - **Protein Binding**: Aprepitant is more than 95% bound to plasma proteins. - **Volume of Distribution**: The mean apparent volume of distribution at steady state is approximately 70 L. - **Excretion**: Approximately 57% excreted in urine and 45% in feces, with no unchanged substance excreted in urine. **Clinical Efficacy** Studies have shown that: - Aprepitant in combination effectively controls both acute and delayed symptoms of CINV. - Fosaprepitant has shown improvement over treatment with ondansetron alone. - While dual therapy with ondansetron plus dexamethasone was superior in controlling acute emesis, fosaprepitant was more effective for controlling delayed-phase emesis compared to fosaprepitant plus dexamethasone alone. - A randomized, double-blind study comparing fosaprepitant and aprepitant found their antiemetic effects to be comparable (71.96% vs. 69.35%). **Safety Profile** Both aprepitant and fosaprepitant are generally well-tolerated: - Most adverse events observed are of mild or moderate intensity. - Potential side effects include peeling or blistering of the skin, and urinary issues. - As CYP3A4 inhibitors, they may interact with other medications metabolized through this pathway. - Special precautions for patients with liver disease or those who are pregnant, planning to become pregnant, or breastfeeding. **Administration** Aprepitant injection or fosaprepitant injection is usually given as a one-time dose on day 1 of a chemotherapy treatment cycle, finishing about 30 minutes before chemotherapy begins. Fosaprepitant was the first intravenous single-dose NK1 receptor antagonist approved in the US for both highly emetogenic chemotherapy and moderately emetogenic chemotherapy. **Guidelines** Both medications are recommended in clinical guidelines for preventing CINV due to moderately and highly emetogenic chemotherapy. The Multinational Association of Supportive Care in Cancer (MASCC) and National Comprehensive Cancer Network (NCCN) clinical guidelines support the bioequivalence of these drugs and advise that they may be used interchangeably on the first day of intervention for acute CINV.