ANTIEMETICS: NEW DEVELOPMENTS

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ANTIEMETICS NEW DEVELOPMENTS

• Fausto Roila
• Medical Oncology Division, Perugia, Italy

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ANTIEMETICS OF CHOICE

• Cisplatin
• - acute emesis NK1 5-HT3 DEX
• - delayed emesis NK1 DEX or
• DEX MTC or
• DEX 5-HT3
• Moderately emetogenic chemotherapy
• - acute emesis 5-HT3 DEX ?NK1
• - delayed emesis NK1 or DEX

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Complete protection from vomiting with antiemetic
prophylaxis
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NEW ANTIEMETICS

• PALONOSETRON
• CASOPITANT
• OLANZAPINE
• MIDAZOLAM
• GABAPENTIN
• GHRELIN

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PALONOSETRON
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PALONOSETRON

• Potent and selective 5-HT3 antagonist
  
• with a high affinity for 5-HT3 receptors.
• Mean plasma elimination T½ of 40 h
• T½ of other 5-HT3 antagonists is 4-8 h.

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PALONOSETRON

• Metabolized primarily by CYP2D6 and to
  a lesser extent by CYP3A and CYP1A2.
• No difference in metabolism between poor and
  extensive metabolisers of CYP2D6 substrates.
• Age, hepatic dysfunction or mild-to-moderate
  renal impairment have no clinically significant
  effect on the pharmacokinetics of palonosetron.

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PALONOSETRON IN CISPLATIN-TREATED PATIENTS
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EFFICACY, SAFETY AND PHARMACOKINETICS OF
PALONOSETRON IN PATIENTS RECEIVING HIGHLY
EMETOGENIC CISPLATIN-BASED CHEMOTHERAPY A
DOSE-RANGING CLINICAL STUDY
Eisenberg P et al. Ann Oncol 2004
15 330-337
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RESULTS
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A PHASE III, DOUBLE-BLIND, RANDOMIZED TRIAL OF
PALONOSETRON COMPARED WITH ONDANSETRON IN
PREVENTING CHEMOTHERAPY-INDUCED NAUSEA
AND VOMITING FOLLOWING HIGHLY EMETOGENIC
CHEMOTHERAPY Aapro
MS et al. Ann Oncol 2006 171441-449
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Complete Response Acute and Delayed Emesis
Complete Response (CR) no emesis, no rescue
medication.
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PALONOSETRON IN PATIENTS SUBMITTED TO MODERATELY
EMETOGENIC CHEMOTHERAPY
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PALONOSETRON IMPROVES PREVENTION OF
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
FOLLOWING MODERATELY EMETOGENIC CHEMOTHERAPY
RESULTS OF A DOUBLE-BLIND RANDOMIZED PHASE III
TRIAL COMPARING SINGLE DOSES OF PALONOSETRON WITH
ONDANSETRON Gralla RJ
et al. Ann Oncol 2003 141570-77
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IMPROVED PREVENTION OF MODERATE
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH
PALONOSETRON, A PHARMACOLOGICALLY NOVEL 5-HT3
RECEPTOR ANTAGONIST RESULTS OF A PHASE III
SINGLE-DOSE TRIAL VERSUS DOLASETRON
Eisenberg P et al.
Cancer 2003 98 2473-82
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Complete Response Acute and Delayed Emesis
97.5 CIs and two-sided Fishers exact test
(significance level 0.025) indicate a
difference between palonosetron and ondansetron.
Complete Response (CR) no emesis, no rescue
medication.
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Complete Response Acute and Delayed Emesis
97.5 CIs and two-sided Fishers exact test
(significance level 0.025) indicate a
difference between palonosetron and ondansetron.
Complete Response (CR) no emesis, no rescue
medication.
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SHORTCOMINGS OF THE STUDIES

• DEX was given to 0, 5 and 67 only
• 30-60 of pts pretreated
• No prophylaxis for delayed emesis
• Can we conclude that PALO is superior
• when a non-inferiority design was used?

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TOLERABILITY

• Palonosetron is well tolerated
• Adverse events are similar to other
  5-HT3 antagonists

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CONCLUSIONS

• Palonosetron in three well conducted double-blind
  studies demonstrated similar efficacy as
  ondansetron in cisplatin-treated patients and was
  superior to ondansetron and dolasetron in
  patients submitted to moderately emetogenic
  chemotherapy.
• Palonosetron should be evaluated with respect to
  the other 5-HT3 antagonists when combined with
  dexamethasone (and aprepitant).

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COMBINATION THERAPY FOR CHEMOTHERAPY-INDUCED
NAUSEA AND VOMITING IN PATIENTS RECEIVING
MODERATELY EMETOGENIC CHEMOTHERAPY PALONOSETRON,
DEXAMETHASONE, AND APREPITANT Grote T et al.
J Support Oncol 2006 4403-8
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Palonosetron Aprepitant Dexamethasone
Complete Response (N58)
100
88
78
78
80
60
( of Patients)
40
20
0
Acute 0-24
Delayed 24-120
Overall 0-120
Time (hr)

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PREVENTION OF MODERATELY EMETOGENIC
CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING WITH A
1-DAY 3-DRUG ANTIEMETIC REGIMEN PRELIMINARY
REPORT Grunberg S et al. Support Care Cancer
2006 14596-7
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Results (n 15)

• Chemotherapy doxorubicin
  cyclophosphamide
• Antiemetics palonosetron 0.25 mg iv
• aprepitant 285 mg po
• dexamethasone 20 mg po
  
• Day 1 Days 2-5
• Complete response 80 47
• No emesis 100 100
• 
  

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CASOPITANT
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CASOPITANT

• It is a potent and selective oral NK1 receptor
  antagonist which has shown activity in preventing
  chemotherapy-induced nausea and vomiting in
  preclinical studies
• Based on phase I positron emission tomography
  studies, casopitant doses from 50 - 150 mg result
  in 70 - 95 saturation of NK1 receptors

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MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
ONDANSETRON-CONTROLLED, DOSE-RANGING, PARALLEL
GROUP TRIAL OF THE NEUROKININ-1 RECEPTOR
ANTAGONIST CASOPITANT MESYLATE FOR
CHEMOTHERAPY-INDUCED NAUSEA / VOMITING IN
PATIENTS RECEIVING MODERATELY EMETOGENIC
CHEMOTHERAPY Arpornwirat W, et al. Proc. ASCO
2006 24471s (ab.8512)
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Results (n 719)

• ANTIEMETICS OND 8 mg x 2 day 1-3
• Dex 8 mg x 1 day 1
• CR ()
• - placebo
  70
• - casopitant 50 mg po day 1-3
  81
• - casopitant 100 mg po day 1-3 79
• - casopitant 150 mg po day 1-3
  85
• - casopitant 150 mg day 1
  80
• Ond 16 mg po day 1-3 Dex 8 mg iv day 1
  84
• casopitant 150 mg po day 1-3

p0.0124
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RANDOMIZED PHASE II TRIAL OF THE NEUROKININ-1
RECEPTOR ANTAGONIST CASOPITANT MESYLATE WITH
ONDANSETRON / DEXAMETHASONE FOR
CHEMOTHERAPY-INDUCED NAUSEA / VOMITING IN
PATIENTS RECEIVING HIGHLY EMETOGENIC CHEMOTHERAPY
Rolski J et al. Proc. ASCO 200624471s
(ab.8513)
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Results (n 493)

• ANTIEMETICS OND 32 mg x 1 day 1
• Dex 8 mg x 1 day 1-4
• CR ()
• - placebo
  60
• - casopitant 50 mg po day 1-3
  76
• - casopitant 100 mg po day 1-3 86
• - casopitant 150 mg po day 1-3
  77
• - casopitant 150 mg day 1
  75
• - aprepitant 125 mg po day 1 and 80 mg day 2-3
  72
• p0.0036

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OLANZAPINE
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OLANZAPINE

• It is an antipsychotic drug that blocks multiple
  neurotransmitters
• - dopamine at D1, D2, D3 and D4 brain
  receptors,
• - serotonin at 5-HT2a, 5-HT2c, 5-HT3 and 5-HT6
• receptors,
• - catecholamines at alpha 1 adrenergic
  receptors
• - histamine at H1 receptors

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OLANZAPINE

• - Case reports on the use of olanzapine as an
  antiemetic for chronic nausea in advanced
  cancer patients and for opioid-induced nausea
• - In a retrospective chart review of 28 patients
  who received olanzapine on an as-needed basis
  following moderately to highly emetogenic
  chemotherapy, data suggested that olanzapine may
  decrease delayed emesis (Passik SD et al. J Pain
  Symptom Manage 200325485-89)

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A PHASE II TRIAL OF OLANZAPINE FOR THE PREVENTION
OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING A
HOOSIER ONCOLOGY GROUP STUDY
Navari RM, et al. Support Care Cancer
200513529-34
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Phase II trial of olanzapineTreatment
Day 1
Days 2-4
Days -2-1
G
D
O
D
O
O
Ggranisetron Ddexamethasone Oolanzapine
Navari RM et al. Support Care Cancer
200513529-534.
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Phase II trial of olanzapineComplete Response
Complete Response (CR) no emesis, no rescue
medication.
Navari RM et al. Support Care Cancer
200513529-534.
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Phase II trial of olanzapineNo nausea
Complete Response (CR) no emesis, no rescue
medication.
Navari RM et al. Support Care Cancer
200513529-534.
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CONCLUSIONS

• - In this study it seems that olanzapine is safe
  (no grade 3 or 4 toxicities) and effective in
  controlling acute and delayed chemotherapy-induced
  nausea and vomiting in patients receiving highly
  and moderately emetogenic chemotherapy
• - Limitations of the study small number of
  patients and lack of a control arm and,
  therefore, RCT are necessary to define its role

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MIDAZOLAM
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MIDAZOLAM

• Short-acting benzodiazepine with a rapid onset of
  action which has been demonstrated efficacious as
  antiemetic in postoperative emesis resistant to
  the usual treatments
• Midazolam decreases dopamine input at the CTZ or
  dopaminergic neuronal activity and 5-HT release
  by binding to the GABA benzodiazepine
  complex
• In a phase I study in patients submitted to
  chemotherapy the dose for phase II studies
  was defined as 0.04 mg/kg (Potanovich
  LM. J Pain Symptom Manage 19918519-24)

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MIDAZOLAM FOR ACUTE EMESIS REFRACTORY TO
DEXAMETHASONE AND GRANISETRON AFTER HIGHLY
EMETOGENIC CHEMOTHERAPY Mandalà et al. Support
Care Cancer 200513375-80
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Results (n 30)

• Cisplatin-induced acute emesis refractory
  to granisetron and dexamethasone
• Antiemetics
• Gran 3 mg iv Dex 20 mg iv Midazolam
• 0.04 mg/kg 4-hour c.i.
  during chemotherapy
• Results
• 73 of pts had a reduction of at least one
  grade
• (NCI common toxicity criteria) in
  nausea and vomiting intensity in the subsequent
  courses.
• 6 pts (23) had no acute emesis
  during the second course
  

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GABAPENTIN
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GABAPENTIN

• It is a ?-aminobutyric acid analogue approved in
  1994 as an anticonvulsant
• In an anedoctal report, complete resolution of
  chemotherapy-induced nausea was seen in
  a patient with breast cancer, after
  she was placed on gabapentin for the
  treatment of hot flushes

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EFFECT OF GABAPENTIN ON NAUSEA INDUCED BY
CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER
Guttuso T, et al. Lancet 2003 3611703-05
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Results (n 9)

• Patients with moderate nausea after the 1st
  course of adjuvant doxorubicin and
  cyclophosphamide
• Antiemetics
• Ond 16-24 mg iv Dex 20 mg iv ? lorazepam
• 0.5-1 mg iv before chemotherapy
• On course 2nd and 4th gabapentin was
  added
• Results
• 3 pts had complete resolution of nausea during
  gabapentin and 6/9 had at least a 3-point
  reduction (8-point nausea scale) in delayed
  nausea

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GHRELIN
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Rudd JA et al. Neuroscience Letters
200639279-85.
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Is ghrelin involved in antiemesis?

• Ghrelin
• Stimulates gastric motility
• Protects gastric mucosa
• Increases appetite
• Ghrelin receptor mRNA (rats)
• Expression increased in the stomac
  and hypothalamus after cisplatin

Rudd JA et al. Neuroscience Letters
200639279-85.
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Ghrelin and cisplatin-induced emesis
Rudd JA et al. Neuroscience Letters
200639279-85.
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NEW ANTIEMETICS

• PALONOSETRON
• CASOPITANT
• OLANZAPINE
• MIDAZOLAM
• GABAPENTIN
• GHRELIN