84
Notes
APREPITANT: A PROMISING ANTIEMETIC FOR PREVENTION OF
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
Mohammed A. Aseeri
‫يالحظ ثيرظم ظل رضىماظذ رضظتيل ي عالظاً كالمظا ئ ثرىرا رظا ئ ظل ظمب رضاظمثاً ظاً رضؤيرظاً كرض الرظا ىظا ثيظم ر ظا‬
.‫ ياصف ثل ل رضؤيراً كرض الرا انها حظاة ك ظاةم كقايعرظة‬.‫رضجانبرة رضىخرفة كغرم رضىالباضة ضهتر رضناع ل رضعالج‬
‫ في حدكة ع ككشميل ساكة ل درية رضىعاضجة رضكرىرا رة ك ظا رضؤيرظاً كرض الرظا رضى ظاةم‬emesis ‫كيحدث رض الرا رضحاة‬
‫ ظا رض الرظا‬.‫ع ككشميل ساكة ل دء رضىعاضجة رضكرىرا رة كيد يا ىم ضىظد قصظل لضظذ سظباع كرحظد‬
‫فربد عد مك‬
‫رض ايعي فإنه يحدث يبل رضبدء اضىعاضجة رضكرىرا رة كيحدث ذضك كند رضىماظذ رضظتيل ي ايعظاً حدك ظه حاظ رضىشظهد ك‬
‫ ق ارمظد ناريظل كصظبرة خ عفظة فظي ثظل ظل‬.‫رضمكر ح ك قتثم رضىكاً رضتي حصعت فره ته رضحاضظة ظل رضؤيرظاً كرض الرظا‬
‫رضالنا رضهضىرة كرضجهاز رضعصبي رضىمثزي ي م ل ةالضهظا قاصظرل فاظراضامرا ظمب رضؤيرظاً كرض الرظا رضظتي يظ م حفظزه‬
‫ قشظظىل ظظته رضناريظظل رضعصظظبرة ثظظل ظظل ةك ظظا رل ك راظ ا رل ك سظظر رل ثظظاضرل كسظظرمكقانرل‬.‫ارسظ ة رضعظظالج رضكرىرظظا ي‬
‫ ) رض ي قا م صا باشم كغرم باشم كعذ مثظز رض الرظا رضىامظاة فظي رضجظزء‬substance P( ‫اإلاافة لضذ اة ب‬
‫ كيالظا رضنشظاث رضحرظاي‬.‫رضجانبي رضشبكي ل رضنخاع كقع بظم ظاة ب حظد فظمرة كا عظة رض اثركرنظاب ضعبرب رظدرب رضعصظبرة‬
‫) رضىاماة في ثل ل رضالنظا رضهضظىرة‬NK1( ‫ضهته رضىاة حفز رض الرا رضتي قم قاصرعه ارس ة ا البالب نرا كثرنرل‬
ً‫كرضجهاز رضعصبي رضىمثزي حرث يعع ثل ل ا البالب يا كثرنرل ك ظاة ب ةك ر ئ كراظحا ئ فظي ظدء حظدكث رضؤيرظا‬
.‫كرض الرا رضتي ي م حفزه ارس ة ةكية رضىعاضجة رضكرىرا رة‬
Most patients who undergo chemotherapy have noted that nausea and vomiting are the most
feared and distressing side-effects of cancer treatment (1). Nausea and vomiting from
chemotherapy can be classified as acute, delayed, or anticipatory. Acute emesis generally occurs
within 24 hours of chemotherapy administration; while delayed nausea and vomiting begin 24
hours after chemotherapy and may continue for up to one week. Anticipatory emesis occurs prior
to chemotherapy in patients who anticipate another episode by sight, odors, or memory of the
place where acute nausea and vomiting occurred (2,3). Different neurotransmitters found in the
gastrointestinal tract (GIT) and central nervous system (CNS) mediate the pathophysiology of
chemotherapy-induced nausea and vomiting (CINV).These include dopamine, histamine,
acetylcholine, serotonin, and substance P; which act directly and indirectly on the vomiting center
located in the lateral reticular formation of the medulla (1,4). Substance P is a member of the
tachykinins family of neuropeptides.The biological activity of this substance is to induce vomiting
mediated by neurokinin-1 (NK1) receptors located primarily in the GIT and the CNS (5). Both
NK1 receptors and substance P play a significant role in the pathogenesis of acute and delayed
CINV.
Introduction
The American Society of Clinical Oncology
(ASCO) guidelines suggest that the potential effect
of CINV is influenced by the emetogenicity level of
the chemotherapeutic agent and patient characteristics. Coadministration of chemothera-peutic agents
and repeated cycles of chemotherapy increase the
Department of Pharmacy Practice, North Dakota State University
123D Sudro Hall, Fargo, North Dakota 58105, USA
E-mail: Mohammed.Aseeri@ndsu.edu
Saudi Pharmaceutical Journal, Vol. 14, No. 1 January 2006
risk of CINV. Furthermore, patient characteristics
can increase the risk for CINV; adults under 50 years
old, female patients, children, and those with a
history of motion sickness are more likely to have
CINV (6, 7). Currently an antagonist of 5-hydroxytryptamine 3 receptors (5-HT3) (e.g. ondansetron) in
combination with oral dexametha-sone is used to
control acute emesis after highly emetogenic
chemotherapy (3). However, the 5-HT3 antagonists
do not show efficacy against delayed emesis.
Although the effectiveness of the current antiemetic
agents has controlled and decreased the incidence
APREPITANT
and severity of CINV, nausea and vomiting continue
to occur on a regular basis. The pathophysiology of
delayed emesis is still not completely understood and
difficult to control. It has been estimated that up to
80% of patients receiving cisplation at doses of 50
mg/m² or higher experience delayed nausea and
vomiting despite good control of acute emesis.3
Hence, newer antiemetic agents that can control
delayed emesis are needed.
Aprepitant (Emend®, Merck and Co Inc) is an
antagonist of substance P that blocks NK-1
receptors. This drug was approved by the Food and
Drug Administration (FDA) in April, 2003, for the
prevention of acute and delayed nausea and vomiting
associated with initial and repeat courses of highly
emetogenic cancer chemotherapy, including highdose cisplatin (8). It represents a new class of
antiemetics, the NK-1 receptor antagonists.
Aprepitant in combination with other antiemetics
such as 5-HT3 antagonists and oral dexamethasone
has demonstrated efficacy in the control of both
acute and delayed nausea and vomiting for patients
receiving
highly
emetogenic
chemotherapy.
Approval of aprepitant by the FDA was based on
two multicenter, randomized, parallel, double-blind,
controlled clinical studies. More than 1100 cancer
patients receiving a chemotherapy course with highdose cisplatin ≥ 70 mg/ m² were randomized to
either the aprepitant regimen (N=550) or the
standard therapy (N=555); the primary endpoint was
to achieve a complete response (defined as no emetic
episode and no use of rescue therapy) during the
five-day period after cisplatin therapy. The
aprepitant regimen consisted of an oral dose of
aprepitant 125 mg, an intravenous dose (IV) of
ondansetron 32 mg (5-HT3 antagonist), and oral
dexamethasone 12 mg on Day1; oral aprepitant 80
mg and an oral dexamethasone 8 mg once daily on
Day 2-3; and oral dexamethasone 8 mg on Day 4.
This regimen was compared with standard therapy
which included oral dexamethasone 20 mg plus IV
ondansetron 32 mg on Day 1, and oral
dexamethasone 8 mg twice daily on Day 2-4. Both
studies found that the percentage of patients who
achieved complete response on day 1 to day 5 was
significantly higher in the aprepitant groups versus
the standard therapy [study 1 (72.7% vs. 52.3%);
study 2 (62.7% vs. 43.3%), respectively] (5, 9). The
frequency of delayed emesis was significantly
improved in the aprepitant group compared to
standard therapy 75.4% vs. 55.8%, respectively, in
Saudi Pharmaceutical Journal, Vol. 14, No. 1 January 2006
85
the first study and 67.7% vs. 46.8%, respectively in
the second study (both studies were P<0.001). Based
on data obtained from these two studies researchers
concluded that aprepitant in combination with a
5HT-3 antagonist and dexamethasone has a
significant effect and provides superior antiemetic
protection against CINV associated with highly
emetogenic cancer chemotherapy in acute and
delayed emesis compared with standard therapy.
Recent studies noted that the incidence of CINV is
approximately 41% in patients receiving moderately
emetogenic chemotherapy (MEC) (10) such as cyclophosphamide, doxorubicin, and epirubicin. Therefore, more effective treatments to prevent CINV in
patient receiving MEC, especially in those who are
particularly more susceptible to CINV, are needed.
Using aprepitant in patients receiving MEC was
evaluated recently in breast cancer patients treated
with cyclophosphamide-based chemothe-rapy (11).
Results suggested the addition of Emend to
ondansetron and oral dexamethasone improved the
prevention of emesis during the acute and delayed
phases compared to the control regimen of
ondansetron and dexamethasone alone ( 50.8% vs.
42.5%; P=0.019). Due to the lower potential emesis
with MEC agents, the difference between the
aprepitant group and the control group was smaller
compared to highly emetogenic chemotherapy, but it
was still clinically important. Further studies will
determine the appropriateness of using aprepitant
with MEC.
Clinical trials proved that aprepitant is a safe
antiemetic drug, and most of the adverse effects
reported were described as mild to moderate in
intensity: 10-12% of patients experienced fatigue,
asthenia, dizziness, constipation, diarrhea, anorexia,
and hiccups (4). Based on data obtained from studies
done in animals, aprepitant is rated as FDA
pregnancy category B; however, the potential benefit
of using this drug should outweigh the risk (8).
Aprepitant is a moderate CYP3A4 inhibitor;
therefore, caution is recommended in patients
receiving concomitant medications including
chemotherapy agents that are primarily metabolized
by this system (e.g., ifosfamide, cyclophosphamide,
ketoconazole, corticosteroids) (2). Inhibition of
CYP3A4 by aprepitant could result in elevated
plasma concentrations of these concomitant drugs,
leading to serious or life-threatening reactions (8).
Also, this drug is an inducer of CYP2C9 and can
lower levels of warfarin and oral contraceptives.
86
Coadministr-tion of aprepitant with warfarin may
result in a clinically significant decrease in the
International Normalized Ratio (INR); therefore,
INR should be assessed within 7-10 days of therapy
in patient receiving warfarin therapy. In addition, the
efficacy of oral contraceptives may diminish during
and for four weeks following the last dose of
aprepitant. Thus, an alternative form of birth control
should be used for at least one month after the last
dose of aprepitant.(2). Emend undergoes extensive
hepatic metabolism in the liver primarily through
CYP3A4; therefore, use with caution in hepatic
dysfunction is recommended, as data are very limited
in those patients. The metabolized form of this drug
is excreted in urine and feces in approximately equal
parts, and due to this limited amount that is excreted
unchanged in urine, no dose adjustment is necessary
in patients with renal disease or end-stage renal
failure maintained on hemodialysis (4, 8). To date,
safety and effectiveness of aprepitant in pediatric
patients have not been established as most patient in
clinical trials were either adults, or geriatrics.4
Aprepitant comes as a 3-day tripack containing 125
mg capsule for the first day and two 80 mg capsules
for the second and third day. In United States the
average wholesale price of a 3-day course is $312,
which seems costly (12). However, failure to control
CINV after highly emetogenic chemotherapy can
increase health care costs because of the need for
hospitalization or hydration and replacement of
electrolytes lost during vomiting (4). Therefore,
results obtained from clinical trials of using this drug
with 5-HT3 antagonist and dexamethasone in
patients receiving highly emetogenic chemotherapy
may justify the drug cost. Patients should take a 125
mg capsule on the first day 30-60 minutes before
chemotherapy, then 80 mg capsules on day 2 and 3.
Aprepitant must be taken with a 5-HT3 antagonist
and dexamethasone for 3 days with each cycle of
chemotherapy. Pharmacists are in a position to
provide accurate and useful information to patients
regarding drug therapy. Patients should be counseled
about the dosing schedule of aprepitant, and not to
take the drug alone to prevent CINV, also most
common adverse effects of aprepitant use should be
reviewed. Aprepitant may interact with some drugs
include non-prescription and herbal supplements;
therefore, patients should be advised to inform their
doctor if they start or stop any medications. Women
Saudi Pharmaceutical Journal, Vol. 14, No. 1 January 2006
ASEERI
who use oral contraceptives should be instructed to
use alternative or back-up methods of contraception
during and for one month after the last dose.
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