Introduction

Aprepitant is a neurokinin-1 receptor antagonist that, in combination with a glucocorticoid and a 5HT3 receptor antagonist, is very effective in preventing chemotherapy-induced nausea and vomiting. At therapeutic doses it is also a moderate inhibitor of CYP3A4.

Aprepitant has been initially evaluated in four phase III double-blind randomized studies, three of which involved high-dose cisplatin and one with chemotherapy containing an anthracycline plus cyclophosphamide for breast cancer. The standard therapy arms contained ondansetron and dexamethasone; in the experimental arm, aprepitant in the currently approved dose and schedule was added to ondansetron and dexamethasone. The addition of aprepitant resulted in an absolute difference in complete response (CR; absence of retching or vomiting and no use of an ‘a(chǎn)s-needed’ antiemetic) of 14%–21% in the cisplatin trials and a difference of 9% with MEC. The lesser difference with MEC was attributed to a lack of effect on nausea with aprepitant; however, for retching or vomiting alone, a similar difference with aprepitant among all phase III studies was demonstrated with a 17% difference achieved with MEC and a 14.3%–22.7% difference with cisplatin. Furthermore, significant improvement with aprepitant was observable in both the acute (first 24 h) and delayed (24–120 h) CINV phases.

Mechanism of action

Aprepitant is a neurokinin-1 (NK-1) RA, which has a different mechanism of action from that of 5-HT3 RA and other antiemetics used to prevent CINV. Aprepitant can selectively block the binding of substance P at the NK-1 receptor in the central nervous system, showing benefit in the control of both acute and delayed CINV[1].

Pharmacokinetics

Aprepitant is used in combination with corticosteroids and 5-HT3 receptor antagonists to prevent CINV associated with highly emetogenic chemotherapy and MEC. Aprepitant improves acute and delayed phase control of vomiting and maintains its efficacy over multiple cycles of chemotherapy. Aprepitant is an oral formulation with ～65% bioavailability; it also has a prodrug, fosaprepitant, which is available as an i.v. preparation. Following oral administration, peak plasma concentrations are achieved in 4 h, and its absorption is not affected by food. Aprepitant is recommended for once-a-day (QD) administration as it has a terminal half-life of 9–13 h. It is indicated for use for a maximum of three consecutive days per chemotherapy cycle at a recommended oral dose of 125 mg on day 1 of treatment 1 h before chemotherapy and 80 mg QD on days 2 and 3. Mild hepatic or renal insufficiency does not affect dosage and adjustments are not required on the basis of age, race, or gender. On the basis of publicly available data, oral aprepitant (125 mg) and i.v. fosaprepitant (115 mg) have similar mean plasma concentrations at 24 h after dose and fosaprepitant up to 150 mg is generally well tolerated. The primary pathway of aprepitant elimination is the CYP3A4. CYP3A is the most abundant isoenzyme expressed in the human liver and small intestine and is involved in the metabolism of various anticancer drugs. In addition to being a substrate, aprepitant has been shown to moderately inhibit CYP3A4 and mildly induce CYP2C9. These findings indicate that possible drug–drug interactions may occur when aprepitant is coadministered with drugs, including anticancer agents, metabolized by either of these enzymes. However, it has been noted through a number of pharmacokinetic studies that the impact of most of these interactions is not clinically significant and leads to dose adjustments in few circumstances.

Side effects

Aprepitant had an overall positive tolerability profile in the studies with the most common adverse events being fatigue, anorexia, dyspepsia, constipation, diarrhea and hiccups. The incidence of at least 1 adverse event was generally similar in patients treated with the aprepitant (80.0%) and placebo (81.3%) regimens (P?=?.79). Myelosuppression, transaminase level elevation, anorexia, peripheral neurotoxicity, and fatigue were the most frequently reported adverse events in both the aprepitant and placebo groups. A grade 3 or 4 adverse event was reported in 25 of 125 patients (20.0%) in the aprepitant group and 15 of 118 patients (12.7%) in the placebo group (P?=?.13). In addition, 2 patients in each group developed grade 4 neutropenia and 1 patient in the placebo group had grade 4 leukopenia. Except for the hematologic and biochemical blood indexes, 3 patients (2.4%) in the aprepitant group and 1 patient (0.8%) in the placebo group had grade 3 diarrhea. None of the grade 3 or 4 adverse events was considered to be associated with aprepitant by the attending clinician. No grade 5 adverse events were reported in either of the groups[2].

References

[1] De-Shen Wang. “Effect of Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Women: A Randomized Clinical Trial.” ACS Central Science (2021): e215250.

[2] M.S. Aapro, C.M. Walko. “Aprepitant: drug–drug interactions in perspective.” Organometallics 21 12 (2010): Pages 2316-2323.