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- Dando, T.M. & Perry, C.M. Drugs (2004) 64: 777. doi:10.2165/00003495-200464070-00013
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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 (Cmax) and time to reach Cmax, 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 56–65% versus 40–49%, acute 79–85% versus 65–75%, delayed 61–67% versus 41–52%). For both complete response and complete protection, the difference between the treatment arms was numerically greater in the overall and delayed phases than the acute phase.
A greater proportion of patients in the aprepitant plus standard therapy arms than in the standard therapy plus placebo arms reported no emetic episodes (overall, acute and delayed, regardless of rescue therapy, p < 0.01). In a phase II study, significantly more patients in the aprepitant arm reported no overall or delayed phase significant nausea (p < 0.01); in the acute phase there was no difference between the treatment groups. In two phase III trials, there was no significant difference between the two treatment arms for overall and delayed phase significant nausea. In these trials, however, significantly more patients in the aprepitant plus standard therapy arms did not require rescue medication (p < 0.05).
The antiemetic efficacy of aprepitant plus standard therapy was maintained for up to six cycles of chemotherapy. In a pooled analysis of two phase III trials, the proportion of patients with no emesis and no significant nausea in the aprepitant plus standard therapy arms was significantly greater than that in the standard therapy plus placebo arms in each treatment cycle (p ≤ 0.006).
In three trials, more aprepitant plus standard therapy recipients than standard therapy plus placebo recipients reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis.
In randomised, double-blind trials in adults, aprepitant plus standard therapy was generally well tolerated. Unless stated otherwise, statistical analyses were not reported for tolerability data. The most common adverse event for patients receiving aprepitant plus standard therapy was asthenia/fatigue, which occurred in 17.2–20% of aprepitant plus standard therapy recipients and 9.5–17% of standard therapy plus placebo recipients. Other adverse events occurring in ≥10% of patients in the aprepitant arms were anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups.
In a dose-finding phase II trial, the incidence of drug-related adverse events in patients receiving aprepitant (125mg day 1, 80mg subsequent days) plus standard therapy was not significantly different to that for those receiving standard therapy plus placebo (27 versus 26%). In two phase III trials, 19.5 and 14.0% of patients in the aprepitant plus standard therapy arms compared with 14.4 and 13.5% in the standard therapy plus placebo arms experienced a drug-related adverse event.
The proportions of patients with a documented serious adverse event were numerically similar in the aprepitant plus standard therapy arms and the standard therapy plus placebo arms of the phase III trials (11.0 versus 9.8% and 16.1 versus 17.0%). In the phase II trial, significantly more patients in the aprepitant plus standard therapy arm than in the standard therapy plus placebo arm experienced serious adverse events (21.5 versus 12.3%, relative risk 1.74, p = 0.032); this difference was attributed to a numerically higher incidence of serious infections or febrile neutropenia in the aprepitant plus standard therapy group. The higher rate of infections in the aprepitant plus standard therapy group was assumed to be because of elevated plasma dexamethasone concentrations, as a result of a pharmacokinetic interaction with aprepitant. In subsequent phase III trials, the dexamethasone regimen was modified and no difference was observed in the incidence of serious infections between treatment arms.
In the three trials, 7.1, 8.0 and 2% of patients in the aprepitant plus standard therapy arms discontinued treatment because of an adverse event, compared with 5.3, 5.3 and 1% in the standard therapy plus placebo arms.
Dosage and Administration
Aprepitant (oral, in combination with a corticosteroid and a serotonin 5-HT3 receptor antagonist) is approved in the US for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy in adults. Aprepitant is not approved for use in children or adolescents. The recommended aprepitant dosage is 125mg administered 1 hour prior to initiating chemotherapy treatment (day 1) and 80mg once daily on days 2 and 3.
Concomitant administration of aprepitant with drugs that are CYP3A4 substrates or inhibitors should be approached with caution because these drugs may interact with aprepitant. Doses of coadministered corticosteroids should be reduced. Coadministration of strong CYP3A4 inducers may decrease the efficacy of aprepitant.
While being treated with aprepitant, patients receiving oral contraceptives should use alternative or back-up contraception and those on long-term warfarin therapy should have their clotting status monitored.
Aprepitant has not been evaluated for longer than 5 days per cycle or for the treatment of established emesis and nausea in patients receiving emetogenic chemotherapy.