Core Evidence - Yorkshire and the Humber Deanery

Report
Fosaprepitant and aprepitant
Dr Adam Hurlow
16/11/11
Fosaprepitant and aprepitant
• Selective neurokinin-1 receptor antagonists
• Aprepitant PO/fosaprepitant IV prodrug
• Fosaprepitant 115mg equivalent to aprepitant
115mg
• Licensed for treatment of chemotherapy
induced nausea and vomiting (CINV) with
highly and moderately emetogenic
chemotherapy
Substance P/NK1R
• Substance P –tachykinin
• Acts on NK1 receptor
• Found in the area postrema (CTZ), nucleus
tractus solitarri (NTS), vomiting centre
• Exogenous Substance P in NTS triggers
vomiting
• Substance P/NK1R within the final common
pathway to regulate vomiting
Pathophysiology of
Chemotherapy-Induced Emesis
CINV
• Acute (post-treatment)
– Occurs within first 24 hours after administration of cancer chemotherapy
• Delayed
–
–
CINV that begins after first 24 hours
May last for 120 hours
• Anticipatory
– Learned or conditioned response from poorly controlled nausea and
vomiting associated with previous chemotherapy
• Breakthrough
–
CINV that occurs despite prophylaxis and requires rescue
• Refractory
– Occurs during subsequent treatment cycles when prophylaxis and/or
rescue has failed in previous cycles
CINV
• 50% of patients receiving high-dose cisplatin
experienced vomiting and 58% experienced
nausea despite standard therapy
• Anthracycline and cyclophosphamide
chemotherapy for breast cancer evoked
vomiting in 41% of patients and nausea in 67%
following ondansetron and dexamethasone
Perception vs. Reality:
Emetogenic Chemotherapy
Highly Emetogenic Chemotherapy
Grunberg S. Cancer. 2004;100:2261-2268.
Moderately Emetogenic Chemotherapy
Fosaprepitant and aprepitant in CINV
• Recommended in following guidelines fro
highly/moderately emetogenic chemotherapy:
• American society of clinical oncology, 2006
• European Society of medical oncology, 2008
• Multinational association of supportive care
in cancer,2008
• National comprehensive cancer network,2008
Emetogenic Potential of Single Antineoplastic
Agents
HIGH
Risk in nearly all patients (> 90%)
MODERATE
Risk in 30% to 90% of patients
LOW
Risk in 10% to 30% of patients
MINIMAL
Fewer than 10% at risk
Evidence base
• Cochrane protocol but no review
• Recent literature reviews Chrisp P Core Evidence 2007;2(1)
& Langford P and Chrisp P Core Evidence 2010:5 77-90
• 2007 - 1 meta-analysis, 13 RCT, 1 case reports
• 2010 – 1 meta analysis, 4 RCT, 2 case reports
• Both concluded – clear evidence adding aprepitant to
dexamethasone plus a serotonin antagonist improves
control of emesis and nausea and reduces need for rescue
medication in patients receiving moderately or highly
emetogenic chemotherapy
• Clear evidence patients more satisfied with their antiemetic
therapy when aprepitant added; less impact of symptoms
on daily activities
Evidence: Aprepitant & standard
therapy (ST) vs. ST and placebo
Acute complete response %
Delayed complete response %
Navari 1999
77 vs. 57 (p =0.004)
52 vs. 16 (p <0.001)
Campos 2001
75 vs. 51 (p<0.01)
41 vs. 22 (p<0.05)
Hesketh 2003
89.2 vs. 78.1 (<0.001)
75.4 vs. 55.8 (<0.001)
Poli-bigelli 2003
82.8 vs. 68.4 (<0.001)
67.7 vs. 46.8
(<0.001)
Gralla 2005
71 vs. 49 (<0.005)
67 vs. 32 (<0.005)
Warr 2005
86 vs. 73 (<0.001)
72 vs 51(<0.001)
Schmoll 2006
87.7 vs 79.3 (<0.005)
74.1 vs 63.1
(<0.004)
Herrington 2008
66.7 -70.4 vs 56.2
63-59.3 vs 31.2
Yeo 2009
72.1 vs 72.6
75.6 vs 67.4
Aprepitant beyond chemo
•
Preventing postoperative nausea and vomiting: post hoc analysis of pooled data
from two randomized active-controlled trials of aprepitant. Current Medical
Research and Opinion2007, Vol. 23, No. 10 , Pages 2559-2565 Diemumsch P et al
- 1599 patients for major surgery under general anaesthesia
- RCT, double blind
- aprepitant 40mg or125mg vs ondansetron 4mg IV pre-op
- no significant nausea (56.4% vs. 48.1%)
- no nausea (39.6% vs. 33.1%)
- no vomiting (86.7% vs. 72.4%)
- no nausea and no vomiting (38.3% vs. 31.4%)
- no nausea, no vomiting, and no use of rescue (37.9% vs. 31.2%)
p < 0.035 for the odds ratio for each comparison
Regimens
• Fosaprepitant (Ivemend)
intravenous infusion, over 20–30
minutes, 150 mg 30 minutes before
chemotherapy on day 1 of cycle only
• Aprepitant (Emend)
125 mg 1 h pre chemotherapy, then 80 mg od
for the next 2 days
Complications
• Aprepitant is eliminated primarily by
metabolism; aprepitant is not renally
excreted.
• Well tolerated in patients with mild to
moderate hepatic insufficiency (Child-Pugh 59). Unknown >9
• No dose adjustment for renal insufficient/HD
• Side effects diarrhoea (23-60%), headache 3%,
infusion site pain 7.6-10.4%
Interactions
• CYP3A4 substrate
- increased by ketocoanzole
- decreased by carbemazapine
• inhibition of CYP3A4 and induction CYP2C9
- increases dex/methylpred levels
- OCP failure
- increases midazolam
- decreases warfarin

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