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Kytril: a once-daily 5HT3 receptor
antagonist for control of
chemotherapy-induced nausea
and vomiting (CINV)
Frederick Schnell
Central Georgia Hematology Oncology Associates
Macon, GA, USA
Nausea and vomiting significantly impact
on patients’ quality of life1
 Following chemotherapy†, nausea/vomiting scored by patients
(n=80) using 5-day diary and 6-day Functional Living Index
 Doctors and nurses (n=9) estimated frequency of acute and
delayed nausea/vomiting
Physicians/nurses
(estimate)
Patients
(actual)
no nausea
69
53
no vomiting
83
72
no nausea
76
43
no vomiting
91
59
Acute (%)
Delayed (%)
†First-cycle
moderately emetogenic chemotherapy
1. Grunberg. Proc Am Soc Clin Oncol 2002;21:250a (Abstract 996)
Nausea and vomiting are rated as major
side-effects of cancer therapy
19831
19952
1
Vomiting
Nausea
2
Nausea
Alopecia
3
Alopecia
Vomiting
Rank
 Following the introduction of 5HT3 receptor
antagonists, the rating of vomiting as a side-effect of
chemotherapy has declined2,3
1. Coates et al. Eur J Cancer Clin Oncol 1983;19:203–8
2. de Boer-Dennert et al. Br J Cancer 1997;76:1055–61
3. Griffin et al. Ann Oncol 1996;7:189–95
Pharmacologic control of vomiting
 Pharmacologic prevention of vomiting is directed at
blocking vomiting pathways before the administration
of chemotherapy or radiotherapy treatments
 Antiemetics may act via the:1
– vomiting center
– chemoreceptor trigger zone
– peripheral receptors (e.g. vagal afferent nerves)
1. Lindley, Blower. Am J Health-Syst Pharm 2000;57:1685–97
Which antiemetic?
 Commonly used agents include:
– dopamine-receptor antagonists
– corticosteroids
– benzodiazepines
– antihistamines
– 5HT3-receptor antagonists
 5HT3-receptor antagonists are currently the
‘gold-standard’ antiemetic1–4
1. Gralla et al. J Clin Oncol 1999;17:2971–94
2. ASHP. Am J Health-Syst Pharm 1999;56:729–64
3. MASCC. Ann Oncol 1998;9:811–19
4. Koeller et al. Support Care Cancer 2002;10:514–22
Optimizing antiemetic treatment
 Awareness must be increased for:
– current guidelines
– evidence supporting guideline recommendations
– incidence of and risk factors for nausea and
vomiting
 Antiemetic treatment must be individualized based on
patients’ cytotoxic treatment and patient-specific
factors
Antiemetic guidelines
 Differences exist in antiemetic guidelines
– ASCO (American Society of Clinical Oncology)
– MASCC (Multinational Association of Supportive
Care in Cancer)
– ASHP (American Society of Health-Systems
Pharmacists)
 Need easy-to-follow, comprehensive consensus
guidelines
 Need guidelines from radiation experts that address
needs of radiation therapy patients
Patients need less complicated, effective
antiemetic therapy
 The majority of cancer patients receiving radiotherapy
are elderly out-patients
– require fast-acting, long-duration oral antiemetics
 Convenient once-daily oral dosing should:
–  patient compliance
–  control of nausea and vomiting
–  patient quality of life
Who is the ‘average’ cancer patient?
 Cancer incidence and mortality greatest in elderly
patients1
– ‘average’ patient >65 years2
– increased incidence of co-morbidities with aging
(>3.6 in patients aged >65 years)3
– increased use of concomitant medications in
patients >65 years
(average medications=4.3 per person)4
1. Yancik, Ries. Hematol Oncol Clin North Am 2000;14:17–23
2. Yancik et al. J Clin Oncol 2001;19:1147–51
3. Yancik. Cancer 1997;80:1273–83
4. Jorgensen et al. Ann Pharmacother 2001;35:1004–9
Chemotherapy- and radiation-induced
emesis in the elderly
 Elderly are more likely to suffer from chemotherapy
and radiotherapy-induced toxicity1
– may have declining organ function
– co-morbidities
– concomitant medications2,3
 Consequences of nausea and vomiting can be
exacerbated in elderly, mainly in patients with
co-morbidities
– dehydration in patients taking diuretics
– exacerbation of cognitive problems
– falls due to extra-pyramidal effects
1. Extermann et al. Hematol Oncol Clin North Am 2000;14:63–77
2. Jorgensen et al. Ann Pharmacother 2001;35:1004–9
3. Hanlon et al. Drugs Aging 2001
Suboptimal antiemetic treatment in the
elderly
 Older patients may receive suboptimal antiemetic
treatment because of:
– gastrointestinal changes1 – decreased drug
absorption
– contraindications to corticosteroids (e.g. with
hypertension, diabetes)2
– swallowing problems1,3
– noncompliance to oral therapies4
– possible cognitive impairment/confusion5
 Patients need a single drug intake per day
1. Orr, Chen. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226–31
2. http://www.geriatricsyllabus.com/syllabus/main.jsp?cid=SCC-DER-4-2
3. Wilkinson, de Picciotto. S Afr J Commun Disord 1999;46:55–64
4. Lebovits et al. Cancer 1990;65:17–22; 5. Schroder et al. J Neural Transm Suppl 1998;54:51–9
Which 5-HT3-receptor antagonist?
 Kytril (granisetron) and ondansetron are currently
indicated for CINV and radiotherapy-induced nausea
and vomiting (RINV)
 Differences exist between Kytril and ondansetron
– underlying pharmacology
– duration of efficacy
– hepatic metabolism
– dose adjustments in hepatically impaired patients
– dosing regimens
Drug-drug interactions
 Kytril
– not shown to induce or inhibit hepatic metabolism1
– only 5-HT3-receptor antagonist not linked to
CYP2D6 genetic polymorphism1
 Ondansetron
– known interactions
• chemotherapeutic agents2
• antidepressants3
• antibiotics4,5
• analgesics6
1. Blower. Cancer J 2002;8:405–14; 2.Cagnoni et al. BMT 1999;24:1–4
3. Stanford, Stanford. J Psychopharmacol 1999;13:313–7
4. www.hivmedicationguide.com/Asp_bin/drug%20interactions.asp
5. www.anaesthetist.com/physiol/basics/metabol/cyp/o.htm
6. DeWitte et al. Anesth Analg 2001;92:1319–21
Hepatic metabolism route
 Kytril has not been shown to induce or inhibit hepatic
metabolism1
CYP1A1
CYP1A2
CYP2D6
CYP3A3/4/5

Granisetron


Dolasetron


Tropisetron

*
Ondansetron
*

*Minor
1. Bower. Cancer J 2002;8:405–14
CYP2D6 polymorphism
 Genetic polymorphism shown to affect cancer
patients’ response to ondansetron and tropisetron
therapy1
 Kytril not at risk for genetic polymorphism
Ultra-rapid metabolizers
(enzyme induction)
Poor metabolizers
(enzyme inhibition)
 Metabolism
 Metabolism
 Efficacy
 Risk of AEs
– genetic testing required to determine true risk
AE = adverse event
1. Kaiser et al. J Clin Oncol 2002;20:2805–11
Cardiovascular warnings
Cardiovascular warning
(prescribing information)
Kytril1

Ondansetron2

Dolasetron3

Tropisetron4

1. Kytril (granisetron hydrochloride) Prescribing Information
2. Zofran (ondansetron hydrochloride) Prescribing Information
3. Anzemet (dolasetron mesylate) Prescribing information
4. Navoban (tropisetron) Prescribing Information
Cardiotoxic effects of 5-HT3-receptor
antagonists in healthy adults
Agent
Dose
ECG changes
Clinical effects
Kytril1
10 µg/kg, i.v. (5 min)
No differences
Ondansetron1
10 µg/kg, i.v. (30 s)
32 mg, i.v. (15 min)
 mean post-dose QTc
Not clinically
significant
interval*
Dolasetron2
1.2, 1.8, 2.4 mg/kg, i.v.  PR, QTc, QRS
intervals**
Dose-related 
in heart rate
Ondansetron2
32 mg, i.v.
 QTc* & JT** intervals
 in heart rate
Kytril3
2 mg, p.o.
Isolated ventricular &
supraventricular ectopic
activity
No sustained
arrhythmias
Dolasetron4
0.6–5.0 mg/kg, i.v.
 PR interval & QRS
 heart rate at
duration
3 mg/kg or over
*p<0.05; **p<0.001
1. Boike et al. Am J Health-Syst Pharm 1997;54:1172–6
2. Benedict et al. J Cardiovasc Pharmacol 1996;28:53–9
3. Gray et al. Aviat Space Environ Med 1996;67:759–61
4. Hunt et al. J Clin Pharmacol 1995;35:705–12
Dosing regimen: Kytril vs ondansetron
 Ondansetron dosed 2–3 times daily
– associated with swallowing problems when
patients are nauseated
 Once-daily Kytril dosing
–  patient compliance
–  patient quality of life
Antiemetic therapy decisions
 Therapy should depend on the unique needs of each
patient:
– age/health
– co-morbidities
– concomitant medications
 Physicians need to be aware that differences exist
between the available 5HT3-receptor antagonists
A rational choice in the elderly
Co-morbidity assessment
Polypharmacy
Drug–drug interactions
Antiemetic selection that limits complications
Reduced risk of toxicity
Increased possibility of clinical efficacy
Kytril vs ‘conventional’/older antiemetics
 Double-blind, placebo-controlled trial
 30 patients undergoing single-fraction total body
irradiation (7.5 Gy) received i.v.:
– Kytril, 3 mg‡
– metoclopramide (20 mg), dexamethasone (6 mg/m2),
lorazepam (2 mg), 1 hour prior to radiotherapy
Kytril
Comparator
p value
Complete response* rate
53%
13%
0.02
No vomiting rate
(24 hours)
60%
13%
0.008
*No vomiting, no more than mild nausea and no rescue medication
‡Off-label dose in the USA
1. Prentice et al. Bone Marrow Transplant 1995;15:445–8
Kytril is effective in patients refractory to
‘conventional’ antiemetics
 Patients (n=15) refractory to treatment with dopaminereceptor antagonists were scheduled to receive Kytril,
1 mg/day p.o.,‡ 1–2 hours prior to further
radiotherapy*
 Results of Kytril therapy
– complete remission of symptoms was observed in
all patients on days 1–3
– immediate remission of nausea and vomiting was
apparent in 33% of patients
*Pelvic, lumboaortic ± iliac/splenic regions or mediastinum radiotherapy
‡Off-label dose
1. Krengli et al. Minerva Med 1996;87:605–8
Kytril vs tropisetron in
pediatric cancer patients
100
Patients (%)
80
p<0.05
88
Kytril
p<0.002
tropisetron
82
74
60
56
40
20
0
Vomiting
Nausea
Aksoylar et al. Pediatr Hematol Oncol 2001;18:397–406
Kytril is well tolerated – adverse events
classed as mild and transient
 Most frequently reported adverse events in clinical
trials with Kytril
Occurrence
Kytril1
comparator2
placebo3
Headache
20%
13%
12%
Asthenia
18%
10%
4%
Constipation
14%
16%
8%
Diarrhea
9%
10%
4%
Dyspepsia
6%
5%
4%
Abdominal pain
4%
6%
3%
Event
12
mg p.o. q.d. (n=1450); 2Metochlopramide/dexamethasone; phenothiazines/
dexamethasone; dexamethasone alone; prochlorperazine (n=599); 3(n=185)
Kytril Prescribing Information, chemotherapy data
RINV – a significant clinical problem
 Over 80% of patients undergoing radiation of the
upper torso will experience nausea and vomiting1
 Fractionated radiotherapy may involve up to
40 fractions over 6–8 weeks, resulting in prolonged
symptoms of emesis2
 Uncontrolled nausea and vomiting may lead patients
to delay or refuse future radiotherapy3
1. Danioux et al. Clin Radiol 1979;30:581–4
2. Feyer et al. Support Care Cancer 1998;6:253–60
3. Laszlo. In: Antiemetics and Cancer Chemotherapy, 1983:1–5
Incidence of nausea and vomiting
 Overall, 38.7% of patients experienced RINV
 Previous chemotherapy increased risk of symptoms
50
p=0.003
45.6%
Patients (%)
40
30
20
10
Previous
chemotherapy
No chemotherapy
33.1%
p=0.028
22.1%
15.1%
0
Vomiting
Nausea
IGARR. Int J Radiat Oncol Biol Phys 1999;44:619–25
Duration of nausea and vomiting
following radiotherapy
Patients experiencing nausea
and vomiting (%)
 The symptoms of RINV can last several hours after
therapy1
60
Upper hemibody (n=88)
50
Lower hemibody (n=101)
40
30
20
10
0
0
60
90
120
150
180
210
240
270
300
330
360
Duration of symptoms (min)
1. Danioux et al. Clin Radiol 1979;30:581–4
Kytril has a 24-hour duration of action
 Kytril has ‘insurmountable’ 5HT3 receptor binding
Kytril 9 hours
Ondansetron 4 hours
Episodes/hour
Cisplatin
Cyclophosphamide
Carboplatin
First-day early-onset emesis
2
First-day late-onset emesis
1
0
0
4
8
12
16
20
Time after chemotherapy administration (hours)
24
Addition of NK1 receptor antagonists improves
efficacy of standard antiemetic regimen
Standard
5HT3/dex
combination
Triple
combination
p value
Day 1 complete
response rate (%)
68.4
82.8
<0.001
Overall 5-day
response rate (%)
43.3
62.7
<0.001
52.3
72.7
<0.001
Poli-Bigelli et al. (n=523)1
Hesketh et al. (n=521)2
Overall 5-day
response rate (%)
1. Poli-Bigelli et al. Cancer 2003;97:3090–8
2. Hesketh et al. J Clin Oncol 2003;21:4112–9
Kytril effective in combination with
steroids and NK1 receptor antagonists
 Combination of 5HT3 receptor antagonist and
dexamethasone improves emetic control but delayed
emesis still problematic
 Addition of neurokinin 1 (NK1) receptor antagonists to
5HT3/dexamethasone extends emetic control
– triple combination is now standard of care
International anti-emetic guidelines
Emetic potential of
therapy
High
Moderate
Low
†
†
Acute emesis
Delayed emesis
5HT3 + Dex + NK1
Dex + NK1
5HT3 + Dex
Dex
Dex + metoclopramide
–
Adapted from Multinational Association for Symptom Control in Cancer
Conclusions
 The 5-HT3-receptor antagonists are effective for the
treatment of RINV
 Kytril (granisetron)
– effective in refractory patients
– more effective than ‘conventional’ antiemetics
– at least as effective as ondansetron
– well tolerated
– once-daily dosing
– low risk for drug-drug interactions
– no cardiovascular warning