Fosaprepitant and aprepitant

Dr Adam Hurlow16/11/11

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

Grunberg S. Cancer. 2004;100:2261-2268.

Highly Emetogenic Chemotherapy 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 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%

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