Aprepitant

Emend (Merck Sharp and Dohme)

80 mg and 125 mg capsules

Approved indication: emetogenic cancer chemotherapy

Australian Medicines Handbook section 12.3

Many anticancer drugs induce nausea and vomiting. Cisplatin is particularly toxic and induces vomiting which can last for days. Although anti-emetic regimens can control some of the symptoms, possibly half the patients treated with highly emetogenic chemotherapy continue to suffer nausea and vomiting.

To address the problem, researchers have looked at the role of substance P in vomiting. This peptide is found in the brain and the gut and its actions are mediated through the neurokinin-1 receptor. Blocking this receptor may prevent vomiting.

Aprepitant is a selective antagonist of the neurokinin-1 receptor which can cross the blood-brain barrier. It has no affinity for serotonin (5HT3 ) or dopamine (D2 ) receptors.

Patients take aprepitant orally once a day for three days, starting one hour before chemotherapy. The drug is slowly absorbed and extensively metabolised. As it has non-linear pharmacokinetics increasing the dose reduces bioavailability and clearance. The metabolism involves cytochrome P450 3A4 so there is a potential for interaction with other drugs, such as midazolam, metabolised by this system. Aprepitant also induces the metabolism of warfarin. The half-life of aprepitant is 9-13 hours.

Aprepitant was tested in a variety of combinations with dexamethasone, granisetron (5HT3 antagonist) and a placebo in 351 patients having cisplatin for the first time. In the first 24 hours after treatment, 80% of the patients given granisetron, dexamethasone and aprepitant had no vomiting compared with 57% of those treated with granisetron and dexamethasone. Delayed emesis was prevented in 63% of the patients taking the three drugs, but in only 29% of those taking granisetron and dexamethasone.1

In this trial there was no extra benefit in giving aprepitant for five days. Another trial therefore compared a three-day regimen with a standard regimen of ondansetron and dexamethasone. The 530 patients had not previously been treated with cisplatin. There was no acute vomiting in 89% of the patients given aprepitant, ondansetron and dexamethasone compared with 78% of those given the standard regimen. Delayed emesis did not occur in 75% of the patients taking aprepitant and 56% of those taking the standard regimen.2 Another randomised placebo-controlled trial produced similar results.3

As patients with cancer usually require several doses of chemotherapy, another trial has studied two regimens of aprepitant given during six cycles of cisplatin. All 202 patients received a standard regimen of ondansetron and dexamethasone. The prevention of emesis declined from 49% to 34% after six cycles in patients treated with the standard regimen. In patients who also took aprepitant, 64% had no vomiting after the first cycle and 59% had no vomiting after the sixth cycle. 4

Assessing adverse events in patients who are given multiple drugs for their cancers can be difficult. Adverse events associated with regimens containing aprepitant include hiccups, asthenia, headache and altered liver function.

Although the efficacy of aprepitant has been proven, questions remain about its role in practice. As treatment guidelines often include metoclopramide for the prevention of delayed emesis, aprepitant should be compared with such regimens. There also needs to be more study of the effectiveness of aprepitant in subsequent cycles of chemotherapy. Although the results of the trial 4 look promising, few patients completed six cycles of chemotherapy. At present aprepitant can only be used with highly emetogenic chemotherapy, including high-dose cisplatin.

References

  1. Campos D, Pereira JR, Reinhardt RR, Carracedo C, Poli S, Vogel C, et al. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 2001;19:1759-67.
  2. Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin - the Aprepitant Protocol 052 Study Group. J Clin Oncol 2003;21:4112-9.
  3. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Ma GJ, Eldridge K, Hipple A, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Cancer 2003;97:3090-8.
  4. de Wit R, Herrstedt J, Rapoport B, Carides AD, Carides G, Elmer M, et al. Addition of the oral NK 1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol 2003;21:4105-11.

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