fosaprepitant and aprepitant dr adam hurlow 16/11/11
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Fosaprepitant and aprepitant
Dr Adam Hurlow16/11/11
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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
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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
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Pathophysiology of Chemotherapy-Induced Emesis
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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
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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
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Perception vs. Reality: Emetogenic Chemotherapy
Grunberg S. Cancer. 2004;100:2261-2268.
Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy
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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
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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
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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
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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
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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
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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
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Complications
• Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted.
• Well tolerated in patients with mild to moderate hepatic insufficiency (Child-Pugh 5-9). Unknown >9
• No dose adjustment for renal insufficient/HD• Side effects diarrhoea (23-60%), headache 3%,
infusion site pain 7.6-10.4%
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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