Aprepitant

Abstract

Aprepitant (Emend®) is the first commercially available drug from a new class of agents, the neurokinin NK₁ receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults. In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125mg day 1, 80mg once daily on days 2 and 3 or 2–5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63–73% versus 43–52%, p < 0.01 for all comparisons). Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy. Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis. Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used. In conclusion, when added to standard therapy (a serotonin 5-HT₃ receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer. Aprepitant is a selective high-affinity neurokinin NK₁ receptor antagonist which crosses the blood-brain barrier in humans. Aprepitant competitively binds the NK₁ receptors in the brain, thereby blocking the effects of substance P (the natural ligand) in the CNS. The drug has little or no affinity for other neurokinin receptors, rabbit L-type calcium channels, or the receptors targeted by other agents for chemotherapy-induced nausea and vomiting (CINV). In ferrets receiving cisplatin, aprepitant has shown acute- and delayed-phase antiemetic activity and augmented the antiemetic effects of ondansetron and dexamethasone. The pharmacokinetics of aprepitant are non-linear across the recommended dose range (recommended regimen 125mg on day 1, 80mg on days 2 and 3). Following this dosage, the area under the concentration-time curve, maximum plasma concentration (C_max) and time to reach C_max, respectively, were 19.6 μg · h/mL, 1.6 μg/mL and ≈4 hours on day 1 and 21.2 μg · h/mL, 1.4 μg/mL and ≈4 hours on day 3. Aprepitant is extensively metabolised in the liver. Based on in vitro data using human liver microsomes, aprepitant is metabolised mainly by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP1A2 and CYP2C19. The apparent plasma clearance and apparent terminal elimination half-life ranged from 62 to 90 mL/min and 9 to 13 hours. Aprepitant does not have clinically relevant effects on the pharmacokinetics of the serotonin 5-HT₃ receptor antagonists ondansetron and granisetron. It is unlikely to interact with substrates for the p-glycoprotein transporter. Aprepitant is a substrate for, and a moderate inhibitor and inducer of, CYP3A4; it is also an inducer of CYP2C9. Coadministration of aprepitant can increase the plasma concentration of CYP3A4 substrates and decrease the plasma concentration of CYP2C9 substrates. Concomitant administration of aprepitant with CYP3A4 inhibitors may increase the plasma concentrations of aprepitant, while concurrent administration with drugs that strongly induce CYP3A4 activity may reduce the plasma aprepitant concentration. In three multicentre, randomised, double-blind, placebo-controlled trials in adults, aprepitant (125mg day 1, 80mg days 2 and 3 or 2–5) plus standard therapy (intravenous ondansetron and oral dexamethasone) showed efficacy superior to that of standard therapy plus placebo for the primary endpoint, overall complete response (defined as no emesis and no rescue therapy during 0–120 hours postcisplatin, 63–73% versus 43–52%, p < 0.01). Complete responses were also significantly higher with aprepitant plus standard therapy than standard therapy plus placebo during both the acute (83–89% versus 68–78%) and delayed phases (68–75% versus 45–56%). Complete protection (no emesis, no rescue therapy and no significant nausea) during the overall, acute and delayed phases was observed in significantly more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms (overall...