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Title: ANTIEMETICS: NEW DEVELOPMENTS


1
ANTIEMETICS NEW DEVELOPMENTS
  • Fausto Roila
  • Medical Oncology Division, Perugia, Italy

2
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

3
Complete protection from vomiting with antiemetic
prophylaxis
4
NEW ANTIEMETICS
  • PALONOSETRON
  • CASOPITANT
  • OLANZAPINE
  • MIDAZOLAM
  • GABAPENTIN
  • GHRELIN

5
PALONOSETRON
6
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.

7
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.

8
PALONOSETRON IN CISPLATIN-TREATED PATIENTS
9
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
10
RESULTS
11
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
12
Complete Response Acute and Delayed Emesis
Complete Response (CR) no emesis, no rescue
medication.
13
PALONOSETRON IN PATIENTS SUBMITTED TO MODERATELY
EMETOGENIC CHEMOTHERAPY
14
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
15
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
16
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.
17
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.
18
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?

19
TOLERABILITY
  • Palonosetron is well tolerated
  • Adverse events are similar to other
    5-HT3 antagonists

20
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).

21
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
22
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)

23
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
24
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


25
CASOPITANT
26
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

27
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)
28
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
29
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)
30
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

31
OLANZAPINE
32
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

33
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)

34
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
35
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.
36
Phase II trial of olanzapineComplete Response
Complete Response (CR) no emesis, no rescue
medication.
Navari RM et al. Support Care Cancer
200513529-534.
37
Phase II trial of olanzapineNo nausea
Complete Response (CR) no emesis, no rescue
medication.
Navari RM et al. Support Care Cancer
200513529-534.
38
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

39
MIDAZOLAM
40
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)

41
MIDAZOLAM FOR ACUTE EMESIS REFRACTORY TO
DEXAMETHASONE AND GRANISETRON AFTER HIGHLY
EMETOGENIC CHEMOTHERAPY Mandalà et al. Support
Care Cancer 200513375-80
42
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

43
GABAPENTIN
44
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

45
EFFECT OF GABAPENTIN ON NAUSEA INDUCED BY
CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER
Guttuso T, et al. Lancet 2003 3611703-05
46
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

47
GHRELIN
48
Rudd JA et al. Neuroscience Letters
200639279-85.
49
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.
50
Ghrelin and cisplatin-induced emesis
Rudd JA et al. Neuroscience Letters
200639279-85.
51
NEW ANTIEMETICS
  • PALONOSETRON
  • CASOPITANT
  • OLANZAPINE
  • MIDAZOLAM
  • GABAPENTIN
  • GHRELIN
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