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Fosaprepitant and aprepitant

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

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Fosaprepitant and aprepitant

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  1. Fosaprepitant and aprepitant Dr Adam Hurlow 16/11/11

  2. 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

  3. 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

  4. Pathophysiology of Chemotherapy-Induced Emesis

  5. 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

  6. 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

  7. Perception vs. Reality: Emetogenic Chemotherapy Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy Grunberg S. Cancer. 2004;100:2261-2268.

  8. 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

  9. Emetogenic Potential of Single Antineoplastic Agents

  10. 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

  11. Evidence: Aprepitant & standard therapy (ST) vs. ST and placebo

  12. 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 Pet 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

  13. 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

  14. 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%

  15. 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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