Introduction

Aprepitant is a substance P/NK1-receptor antagonist, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-l,2,4-triazol-3-one. The compound is a white to off-white crystalline solid (Figure 1) and has a molecular weight of 534.43 Da. It is highly insoluble in water, sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile. Each capsule of Emend? contains either aprepitant 80 or 125 mg and the following inactive ingredients:sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin and titanium dioxide. The 125-mg capsule also contains red ferric oxide and yellow ferric oxide.The current market version of Emend? capsules contains the drug as a nanoparticle formulation. Initially in the clinical development of aprepitant, a tablet formulation (L-754,030)was used that was more susceptible to food effects and had lower bioavailability. Thus, some of the earlier Phase II trials report higher doses of aprepitant (due to the use of the older tablet formulations). This tablet formulation has been modified to the current nanoparticle formulation that has a higher bioavailability and reduced food effect. Additionally, a water soluble intravenous prodrug (L-758,298) of aprepitant was developed. This formulation is rapidly and completely converted to aprepitant in vivo and was used in earlier clinical studies. L-758,298 was not developed for market use. [1]

Mechanism of action

Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis. Along with a unique mechanism of action, aprepitant also has favorable pharmacokinetic properties. [2]

Pharmacodynamics properties

Aprepitant is highly selective for the NK1 receptor and inhibits the binding of substance P at this receptor (inhibitory concentration [IC]50 0.1nM). When aprepitant and its intravenous prodrug, L-758,298, were administered to ferrets,both agents demonstrated good efficacy against cisplatin-induced retching and vomiting. The ferret model was chosen for the preclinical studies because this animal exhibits a similar emetic profile to humans, and most importantly, displays both acute and delayed emesis from cisplatin. Aprepitant offers a novel approach for the prevention of nausea and vomiting in that it has a different mechanism of action from currently available antiemetics and acts primarily centrally.[1]

Pharmacokinetics and metabolism

After oral administration of a single 40 mg dose in healthy volunteers, area under the curve (AUC) was 7.8 μg*h/mL with a maximum plasma concentration (Cmax) of 0.7 μg/mL that was reached around 3 hours after dosing (Tmax).Aprepitant is greater than 99% bound to plasma proteins with a volume of distribution of 70L. Metabolism is primarily mediated by hepatic CYP3A4 with minor metabolism via CYP1A2 and CYP2C19 enzymes that produce weak metabolites. In patients with renal or hepatic impairment,there has been no meaningfully demonstrated clinical differences. Aprepitant metabolites are excreted in the urineand feces. Aprepitant’s half-life is estimated to be between 9.4–13.2 hours. In pediatric patients (birth to 17 years of age), aprepitant demonstrates a pharmacokinetic dose-exposure relationship and is well tolerated with no significant adverse effects identified to date.Currently, aprepitant is available orally in 40 mg, 80 mg or125 mg formulations. The 40 mg dose is the one approved for prophylaxis of PONV, and it must be administered within 3hours of anesthesia as it will reach maximum plasma concentration withing 3 hours. Although commonly prescribed orally, two other forms of aprepitant are available.Fosaprepitant is a water-soluble phosphoryl prodrug of aprepitant that is available at 150 mg for intravenous administration. After administration, fosaprepitant is converted to aprepitant within 30 minutes. Fosaprepitant is FDA approved for the management of chemotherapy-induced nausea and vomiting (CINV), but not for PONV. Aponvie, the recently approved IV formulation of aprepitant, is prescribedat 32 mg over a 30 second injection prior to induction of anesthesia. It reaches therapeutic plasma concentrations associated with at least 97% receptor occupancy within 5 minutes of administration. The approval of HTX-019 (Aponvie) was based on a randomized open-label phase 1 cross over study in 32 healthy volunteers. The study reported that the administration of a 32 mg dose as a 30 second intravenous injection had bioequivalent pharmacokinetics to those of oral aprepitant 40 mg. Investigation of a nanoparticle formulation of aprepitant using in vitro dissolution studies has demonstrated improved solubility and dissolution of the drug. However, a rat single-pass intestinal perfusion model highlighted that intestinal solubility is still a barrier for the nanoparticle formulation with further investigation necessary before more robust in vivo experiments are conducted.The target of aprepitant is the NK-1 receptor which is located throughout the body with an increased density in the central nervous system (CNS), particularly of interest in the area postrema and NTS. When these receptors are bound by substance P, a tachykinin neuropeptide, signals are relayed to the chemoreceptor trigger zone and vomiting center of the brain that may induce vomiting. Aprepitant is a selective,high-affinity NK-1RA that passes through the blood brain barrier and blocks substance P binding to reduce stimulation of vomiting. Positron emission tomography (PET) has demonstrated this binding of NK-1 receptors in healthy human patients. Aprepitant has minimal or no affinity for common antiemetic targets including 5-HT3, dopamine or corticosteroid receptors. [2]

Conclusion

Aprepitant offers a novel approach for the prevention of CINV and clinical trials have consistently demonstrated ~ 20% improvement in response rates for both acute and delayed CINV. Although aprepitant has not been compared with what most clinicians would consider standard therapy for prevention of delayed CINV (5-HT3 antagonist + corticosteroid), the benefits are likely to remain consistent as the5-HT3 antagonists are not thought to offer substantial control of nausea and vomiting during the delayed phase. Aprepitant remains more expensive than other antiemetics,which could limit its use in some practices. There is therefore a need for cost effectiveness studies for the prophylactic use of aprepitant.[1-2]

References

[1] Patel L, Lindley C. Aprepitant--a novel NK1-receptor antagonist. Expert Opin Pharmacother. 2003;4(12):2279-2296. doi:10.1517/14656566.4.12.2279

[2] Padilla A, Habib AS. A pharmacological overview of aprepitant for the prevention of postoperative nausea and vomiting. Expert Rev Clin Pharmacol. 2023;16(6):491-505. doi:10.1080/17512433.2023.2209722