indication

For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents).

pharmacology

Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT₃), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

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.

biotransformation

Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.

absorption

The mean absolute oral bioavailability of aprepitant is approximately 60 to 65%.

half life

9-13 hours

route of elimination

Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk.

drug interactions

Acenocoumarol: Aprepitant may decrease the anticoagulant effect of acenocoumarol by decreasing its serum concentration.

Alprazolam: Aprepitant may increase the effect and toxicity of the benzodiazepine, alprazolam.

Anisindione: Aprepitant may decrease the anticoagulant effect of anisindione by decreasing its serum concentration.

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Carbamazepine: The CYP3A4 inducer, carbamazepine, may decrease the effect of aprepitant.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clarithromycin: The CYP3A4 inhibitor, clarithromycin, may increase the effect and toxicity of aprepitant.

Corticotropin: Aprepitant may increase the serum concentration of Corticosteroids (Systemic). Monitor for increased effects of systemic corticosteroids when coadmininistered with aprepitant; corticosteroid dose reduction may be necessary. The manufacturer of fosaprepitant (a prodrug of aprepitant) states that oral dexamethasone doses should be reduced by 50% when coadministered with a fosaprepitant/aprepitant regimen to achieve dexamethasone concentrations similar to those achieved with dexamethasone alone. Dexamethasone doses used in clinical chemotherapy nausea/vomiting studies with aprepitant reflect this 50% decrease. Similarly, it is recommended that in order to achieve concentrations similar to those achieved with methylprednisolone alone, the intravenous methylprednisolone dose should be reduced by 25% and the oral methylprednisolone dose should be reduced by 50% when given together with a fosaprepitant/aprepitant regimen.

Dexamethasone: Aprepitant may increase the effect and toxicity of dexamethasone.

Dicumarol: Aprepitant may decrease the anticoagulant effect of dicumarol by decreasing its serum concentration.

Diltiazem: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Docetaxel: Aprepitant may change levels of the chemotherapy agent, docetaxel.

Erythromycin: Erythromycin, a moderate CYP3A4 inhibitor, may increase the effect and toxicity of aprepitant.

Ethinyl Estradiol: Aprepitant could decrease the effect of the oral contraceptive

Ethotoin: The CYP3A4 inducer, ethotoin, may decrease the effect of aprepitant.

Etoposide: Aprepitant may change levels of the chemotherapy agent, etoposide.

Fosphenytoin: The CYP3A4 inducer, fosphenytoin, may decrease the effect of aprepitant.

Ifosfamide: Aprepitant may change levels of the chemotherapy agent, ifosfamide.

Imatinib: Aprepitant may change levels of the chemotherapy agent, imatinib.

Irinotecan: Aprepitant may change levels of the chemotherapy agent, irinotecan.

Itraconazole: This CYP3A4 inhibitor, itraconazole, may increase the effect and toxicity of aprepitant.

Ketoconazole: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Mephenytoin: The CYP3A4 inducer, mephenytoin, may decrease the effect of aprepitant.

Mestranol: Aprepitant could decrease the effect of the oral contraceptive

Methylprednisolone: Increases the effect and toxicity of methylprednisolone

Midazolam: Aprepitant may increase the effect and toxicity of the benzodiazepine, midazolam.

Nefazodone: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Nelfinavir: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Paclitaxel: Aprepitant may change levels of the chemotherapy agent, paclitaxel.

Phenytoin: The CYP3A4 inducer, phenytoin, may decrease the effect of aprepitant.

Pimozide: Increased risk of cardiotoxicity and arrhythmias

Rifampin: The CYP3A4 inducer, rifampin, may decrease the effect of aprepitant.

Ritonavir: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Tamsulosin: Aprepitant, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Aprepitant is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Aprepitant. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Aprepitant if Telithromycin is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Tolterodine: Aprepitant may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Aprepitant may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inhibitor, Aprepitant, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Aprepitant is initiated, discontinued or dose changed.

Triazolam: Aprepitant may increase the effect and toxicity of the benzodiazepine, triazolam.

Troleandomycin: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Vinblastine: Aprepitant may change levels of the chemotherapy agent, vinblastine.

Vincristine: Aprepitant may change levels of the chemotherapy agent, vincristine.

Vinorelbine: Aprepitant may change levels of the chemotherapy agent, vinorelbine.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of aprepitant by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of aprepitant if voriconazole is initiated, discontinued or dose changed.

Warfarin: Aprepitant may decrease the anticoagulant effect of warfarin by decreasing its serum concentration.