アプレピタント

Q1: What is the primary mechanism of action of aprepitant?

A1: Aprepitant exerts its antiemetic effect by acting as a selective antagonist of the neurokinin-1 (NK-1) receptor. [, , , , ] This receptor, primarily located in the central nervous system (CNS), is the primary binding site for substance P, a neuropeptide involved in the transmission of nausea and vomiting signals. [, , ] By blocking substance P from binding to NK-1 receptors, aprepitant effectively disrupts the emetic pathway. []

Q2: What makes aprepitant particularly effective against delayed CINV?

A2: Aprepitant demonstrates prolonged NK-1 receptor occupancy in the CNS, lasting at least 48 hours after a single dose of its prodrug fosaprepitant. [, ] This sustained receptor blockade effectively controls delayed CINV, which typically manifests 2 to 5 days post-chemotherapy. []

Q3: Does aprepitant affect gastric emptying?

A3: While aprepitant effectively controls nausea, there is evidence suggesting that it does not significantly accelerate gastric emptying. [] This suggests its antiemetic action is primarily mediated through central NK-1 receptor antagonism rather than by directly influencing gastric motility.

Q4: What is the molecular formula and weight of aprepitant?

A4: Unfortunately, the provided research papers do not explicitly state the molecular formula and weight of aprepitant. For detailed structural information, it is recommended to consult additional resources like PubChem or DrugBank databases.

Q5: What is fosaprepitant, and how does it relate to aprepitant?

A5: Fosaprepitant is a water-soluble prodrug of aprepitant, meaning it is converted into active aprepitant in the body. [, , , , , ] It is administered intravenously and rapidly metabolized into aprepitant via ubiquitous phosphatases within 30 minutes of administration. [, ] This makes it a suitable alternative for patients who have difficulty tolerating oral medications. [, , ]

Q6: How is aprepitant metabolized?

A6: Aprepitant undergoes extensive metabolism, primarily by cytochrome P450 (CYP) 3A4 enzymes. [, , , , ] It is first metabolized into the active N-dealkylated metabolite (ND-AP), which is further converted into its carbonyl form (ND-CAP). []

Q7: Does food intake influence the bioavailability of aprepitant?

A7: Studies indicate that food does not significantly impact the bioavailability of a single oral dose of aprepitant, suggesting dose adjustments based on food intake are unnecessary. []

Q8: What is the relationship between aprepitant exposure and total bilirubin levels?

A8: A study investigating aprepitant pharmacokinetics in cancer patients revealed a significant correlation between the 120-hour area under the curve (AUC) of aprepitant and total bilirubin levels. [] This suggests that liver function may influence aprepitant exposure, but further investigation is needed to fully elucidate this relationship.

Q9: What are the approved clinical applications of aprepitant and fosaprepitant?

A9: Both aprepitant and fosaprepitant are FDA-approved for preventing CINV in patients undergoing highly emetogenic chemotherapy, typically in combination with a corticosteroid (like dexamethasone) and a 5-HT3 receptor antagonist (like ondansetron). [, , , , , , , ]

Q10: Can a single dose of fosaprepitant effectively prevent CINV?

A10: Yes, clinical trials have demonstrated that a single intravenous dose of fosaprepitant (150 mg) is noninferior to the standard 3-day aprepitant regimen for preventing both acute and delayed CINV in patients receiving high-dose cisplatin. [, , ]

Q11: Is aprepitant effective in preventing CINV in pediatric patients?

A11: While further research is necessary, studies suggest that aprepitant, in combination with standard antiemetic therapy, can be effective in reducing CINV in children and adolescents. [, , , ] One study even reported the safe use of aprepitant in children as young as 11 months old. []

Q12: Are there alternative antiemetic regimens to aprepitant for CINV?

A12: A fixed-dose combination of netupitant (another NK-1 receptor antagonist) and palonosetron (a 5-HT3 receptor antagonist), known as NEPA, has shown comparable efficacy to a 3-day aprepitant regimen in preventing CINV associated with moderately emetogenic chemotherapy. []

Q13: Does aprepitant interact with other medications?

A13: Yes, aprepitant is metabolized by CYP3A4 and can both inhibit and induce this enzyme, potentially leading to drug interactions. [, , , , ] For instance, aprepitant can increase the plasma concentrations of dexamethasone and methylprednisolone. [, , ] It can also decrease the plasma concentrations of drugs metabolized by CYP3A4, such as warfarin and hormonal contraceptives. [, , ]

Q14: Does aprepitant interact with vincristine?

A14: While aprepitant does not appear to cause a clinically significant drug interaction with vincristine that leads to early-onset peripheral neuropathy, there seems to be an increased risk of overall chemotherapy-induced peripheral neuropathy (CIPN) with concomitant use. [] Further research is needed to fully understand this potential interaction.

Q15: Does aprepitant affect prednisolone pharmacokinetics?

A15: A study investigating the co-administration of aprepitant with the R-CHOP chemotherapy regimen, which includes prednisolone, found no significant impact of aprepitant on prednisolone pharmacokinetics. [] This is consistent with previous findings that CYP3A4 inhibitors, like ketoconazole and itraconazole, do not affect prednisolone metabolism, unlike their effect on dexamethasone and methylprednisolone. []

Q16: How does aprepitant interact with voriconazole?

A16: Aprepitant initially inhibits voriconazole metabolism due to its triazole ring, but subsequently induces CYP3A4, leading to increased voriconazole metabolism and potentially subtherapeutic drug levels. [] This interaction highlights the importance of monitoring voriconazole levels when co-administered with aprepitant or fosaprepitant.

Q17: Are there any potential antitumor effects of aprepitant?

A17: While currently used as an antiemetic, preclinical studies suggest that aprepitant may possess antitumor properties through various mechanisms, including antiproliferative, antimetastatic, and pro-apoptotic effects. [, ] Further research is warranted to explore these findings and assess the potential of repurposing aprepitant as an anticancer agent.

Q18: Does aprepitant have any immunomodulatory effects?

A18: Research suggests that aprepitant may possess immunomodulatory properties by decreasing the expression of programmed death 1 (PD-1) on CD4+ T cells and reducing plasma levels of substance P and soluble CD163. [] This indicates a potential role of NK-1 receptor antagonism in modulating monocyte activation during HIV infection, warranting further investigation.