Kytril: a once-daily 5HT3 receptor antagonist for control of

chemotherapy-induced nausea and vomiting (CINV)

Frederick SchnellCentral 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)

Acute (%)

69 53no nausea

no vomiting 83 72

Delayed (%)

no nausea 76 43

no vomiting 91 59

1. Grunberg. Proc Am Soc Clin Oncol 2002;21:250a (Abstract 996)

†First-cycle moderately emetogenic chemotherapy

Nausea and vomiting are rated as major side-effects of cancer therapy

Following the introduction of 5HT3 receptor antagonists, the rating of vomiting as a side-effect of chemotherapy has declined2,3

Rank 19831 19952

1 Vomiting Nausea

2 Nausea Alopecia

3 Alopecia Vomiting

1. Coates et al. Eur J Cancer Clin Oncol 1983;19:203–82. 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;17:2971–942. ASHP. Am J Health-Syst Pharm 1999;56:729–64

3. MASCC. Ann Oncol 1998;9:811–194. 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;14:17–232. Yancik et al. J Clin Oncol 2001;19:1147–51

3. Yancik. Cancer 1997;80:1273–834. 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;14:63–772. 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 day1. Orr, Chen. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226–312. http://www.geriatricsyllabus.com/syllabus/main.jsp?cid=SCC-DER-4-2

3. Wilkinson, de Picciotto. S Afr J Commun Disord 1999;46:55–644. 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 interactionsKytril

– 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;24:1–43. Stanford, Stanford. J Psychopharmacol 1999;13:313–7

4. www.hivmedicationguide.com/Asp_bin/drug%20interactions.asp5. 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

Ondansetron *

Dolasetron

Tropisetron *

*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

– genetic testing required to determine true risk

AE = adverse event

Ultra-rapid metabolizers (enzyme induction)

Metabolism

Efficacy

Poor metabolizers(enzyme inhibition)

Metabolism

Risk of AEs

1. Kaiser et al. J Clin Oncol 2002;20:2805–11

Cardiovascular warning (prescribing information)

Kytril1

Ondansetron2

Dolasetron3

Tropisetron4

Cardiovascular warnings

1. Kytril (granisetron hydrochloride) Prescribing Information2. 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 Not clinically significant

Ondansetron1 10 µg/kg, i.v. (30 s)

32 mg, i.v. (15 min)

mean post-dose QTc 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 duration

heart rate at

3 mg/kg or over*p<0.05; **p<0.001

1. Boike et al. Am J Health-Syst Pharm 1997;54:1172–62. Benedict et al. J Cardiovasc Pharmacol 1996;28:53–93. 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 assessmentPolypharmacy

Drug–drug interactions

Antiemetic selection that limits complications

Reduced risk of toxicityIncreased possibility of clinical efficacy

Kytril vs ‘conventional’/older antiemeticsDouble-blind, placebo-controlled trial30 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 dopamine-receptor 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 inpediatric cancer patients

0

20

40

60

80

100

Vomiting Nausea

Kytril

tropisetron

Pa

tie

nts

(%

)

8882

74

56

p<0.05p<0.002

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

Event 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%

Kytril Prescribing Information, chemotherapy data

12 mg p.o. q.d. (n=1450); 2Metochlopramide/dexamethasone; phenothiazines/ dexamethasone; dexamethasone alone; prochlorperazine (n=599); 3(n=185)

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;30:581–42. 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

0

10

20

30

40

50

Vomiting Nausea

Previouschemotherapy

No chemotherapy

Pa

tie

nts

(%

)

22.1%

45.6%

15.1%

33.1%p=0.028

p=0.003

IGARR. Int J Radiat Oncol Biol Phys 1999;44:619–25

Duration of nausea and vomiting following radiotherapy

The symptoms of RINV can last several hours after therapy1

0

10

20

30

40

50

60

0 60 90 120 150 180 210 240 270 300 330 360

Duration of symptoms (min)

Pat

ien

ts e

xper

ien

cin

g n

ause

a an

d v

om

itin

g (

%)

Upper hemibody (n=88)

Lower hemibody (n=101)

1. Danioux et al. Clin Radiol 1979;30:581–4

Kytril has a 24-hour duration of action

Kytril has ‘insurmountable’ 5HT3 receptor binding

2

1

0

Ep

iso

des

/ho

ur

0 4 8 12 16 20 24

Time after chemotherapy administration (hours)

First-day early-onset emesis

First-day late-onset emesis

CisplatinCyclophosphamideCarboplatin

Kytril

Ondansetron

9 hours

4 hours

Addition of NK1 receptor antagonists improves efficacy of standard antiemetic regimen

Standard 5HT3/dex

combinationTriple

combination p value

Poli-Bigelli et al. (n=523)1

Day 1 complete response rate (%)

68.4 82.8 <0.001

Overall 5-dayresponse rate (%)

43.3 62.7 <0.001

Hesketh et al. (n=521)2

Overall 5-dayresponse rate (%)

52.3 72.7 <0.001

1. Poli-Bigelli et al. Cancer 2003;97:3090–82. 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

Emetic potential of therapy Acute emesis Delayed emesis

High 5HT3 + Dex + NK1Dex + NK1

Moderate 5HT3 + Dex Dex

Low Dex + metoclopramide –

International anti-emetic guidelines†

† 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