Aprepitant

Aprepitant (Emend®) is a neurokinin-1 (NK₁) receptor antagonist that is able to alleviate the emetic effects of substance P. When combined with a standard regimen of a corticosteroid (dexamethasone) and a serotonin 5-HT₃ receptor antagonist (ondansetron), oral aprepitant (125 mg on day 1 then 80 mg once daily on days 2 and 3) was effective in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with single or multiple cycles of highly emetogenic chemotherapy (HEC). This aprepitant regimen was also effective in the prevention of CINV in patients treated with single or multiple cycles of moderately emetogenic chemotherapy (MEC). A single oral dose of aprepitant 40 mg administered prior to patients undergoing abdominal surgery was also effective in the prevention of postoperative nausea and vomiting (PONV). Aprepitant was generally well tolerated. Aprepitant is a recommended option for the treatment of PONV, and when combined with a corticosteroid and 5-HT₃ receptor antagonist is a recommended regimen for the treatment of CINV.

Aprepitant is a selective, high-affinity antagonist at human NK₁ receptors and is consequently able to alleviate the emetic effects of substance P. Aprepitant has little or no affinity for serotonin 5-HT₃, dopamine or corticosteroid receptors. Aprepitant crosses the blood-brain barrier. Aprepitant had no effect on gastrointestinal motor function in healthy volunteers.

The pharmacokinetics of aprepitant are nonlinear across the recommended dose range, with clearance and absolute bioavailability decreasing with increasing dose. Following administration of a single oral dose of aprepitant 40 mg (recommended dosage in the prevention of PONV) to healthy volunteers, the area under the plasma concentration-time curve (AUC) from time zero to infinity was 7.8 mg · h/mL and the maximum plasma concentration (C_max) was 0.7 μg/mL. The median time to C_max (t_max) was ≈3.0 hours. Following administration of oral aprepitant 125 mg on day 1 followed by 80 mg once daily on days 2 and 3 (recommended dosage in the prevention of CINV) to healthy volunteers, the AUC from 0 to 24 hours, the C_max and t_max were 19.6 μg · h/mL, 1.6mg/mL and ≈4 hours, respectively, on day 1 and 21.2 μg · h/mL, 1.4 μg/mL and ≈4 hours, respectively, on day 3. Aprepitant is excreted largely as metabolites in the urine and via biliary excretion in the faeces. The apparent terminal half-life was 9–13 hours.

Since aprepitant is metabolized by cytochrome P450 (CYP) 3A4, coadministration of aprepitant and inhibitors or inducers of this isoenzyme will induce changes in the plasma levels of aprepitant. As a moderate inhibitor of CYP3 A4, aprepitant can increase plasma concentrations of coadministered substances that are metabolized through CYP3A4. As a moderate inducer of CYP2C9 and a mild inducer of CYP3A4, aprepitant can decrease plasma concentrations of substrates metabolized by these isoenzymes.

In phase III studies in patients with solid tumours treated with a single cycle of HEC, an aprepitant regimen (containing aprepitant 125 mg on day 1 then 80 mg once daily on days 2 and 3 plus dexamethasone and ondansetron) resulted in significantly higher complete response (no emesis and no rescue therapy) rates than with the control regimen of ondansetron plus dexamethasone (63–73% vs 43–61%; p<0.01) during the overall (day 1–5) phase after HEC administration. Complete response rates during the acute phase (day 1; 83–89% vs 68–79%) and the delayed phase (days 2–5; 68–75% vs 47–63%) were also significantly higher with the aprepitant than with the control regimen. In particular, the rate of no emesis was significantly higher with the aprepitant than the control regimen during the acute, delayed and overall phases. In a multiple-cycle extension study in which patients received of up to five additional cycles of HEC, the efficacy of the aprepitant regimen was maintained throughout each of the multiple cycles.

In patients with breast cancer treated with MEC (cyclophosphamide ± anthracycline), an aprepitant regimen (aprepitant plus dexamethasone plus ondansetron), compared with a control regimen (dexamethasone plus ondansetron) resulted in more patients achieving a complete response during the overall phase (51% vs 42%; p = 0.015), according to data from a large phase III trial. The between-group difference in complete response rates was primarily driven by the rate of no emesis (76% vs 59%; unadjusted p-value < 0.001), with no significant between-group difference for the use of rescue medication. In a multiple-cycle extension of this trial, the advantage of the antiemetic effect of the aprepitant regimen over the control regimen seen in the first cycle was maintained throughout the additional three cycles of MEC. In a large phase III trial in patients with a variety of malignancies receiving MEC, significantly more recipients of a single cycle of an aprepitant than a control regimen had no emesis (76% vs 62%; p < 0.001) and a complete response (69% vs 56%; p < 0.001) during the overall phase.

An aprepitant regimen compared with a control regimen was considered to be cost-effective with regard to the cost per QALY in the prevention of CINV in two European studies, although not according to a US analysis.

Although a large phase III trial failed to prove that a single dose of oral aprepitant 40 mg was superior to ondansetron in preventing PONV (as measured by the proportion of patients with complete response in the 24 hours after surgery), a second phase III trial of similar design established that a single dose of aprepitant 40 mg was noninferior to ondansetron, with 64% versus 55% of patients achieving a complete response. Aprepitant was significantly more effective than ondansetron at preventing vomiting in the 24 and 48 hours after surgery in both studies (p<0.001).

An antiemetic regimen containing dexamethasone, ondansetron and aprepitant (administered administered orally as a single 125 mg dose on day 1 and then 80 mg once daily on days 2 and 3) was generally well tolerated when used in the prevention of CINV in cancer patients receiving single or multiple cycles of HEC or MEC. The incidence of adverse events in recipients of an aprepitant regimen was similar to that in recipients of the control regimen (dexamethasone plus ondansetron). Commonly reported adverse events (≥10% of recipients) were asthenia/fatigue, nausea, hiccups, constipation, diarrhoea and anorexia. Laboratory adverse events (≥3% of recipients) included proteinuria and increases in ALT, AST, blood urea nitrogen and serum creatinine. The adverse event profile of an aprepitant regimen in patients receiving MEC was generally similar to that reported in patients receiving HEC.

The tolerability profile of a single oral dose of aprepitant 40 mg when used in the prevention of PONV was similar to that of a single intravenous dose of ondansetron in patients undergoing open, abdominal surgery who participated in two, large, well controlled studies. Most adverse events were mild to moderate in intensity. Commonly reported adverse events (≥5% of recipients of either treatment group) were constipation, nausea, pruritus, pyrexia, hypotension, headache and flatulence.