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

4. 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

5. Pathophysiology of Chemotherapy-Induced Emesis
Two sites in the brainstem—the vomiting center and the chemoreceptor trigger zone—are important to emesis control. The vomiting center consists of an intertwined neural network in the nucleus tractus solitarius that controls patterns of motor activity. The chemoreceptor trigger zone, located in the area postrema, is the entry point for emetogenic stimuli.
Enterochromaffin cells in the gastrointestinal tract respond to chemotherapy by releasing serotonin. Serotonin binds to 5-HT3 receptors, which are located not only in the gastrointestinal tract, but also on vagal afferent neurons and in the nucleus tractus solitarius and the area postrema.
The activated 5-HT3 receptors signal the chemoreceptor trigger zone via pathways that may include the afferent fibers of the vagus nerve. Serotonin also may bind with 5-HT3 receptors in the brainstem.
Other neurotransmitters, including dopamine and substance P, also influence the chemoreceptor trigger zone. Afferent impulses from the chemoreceptor trigger zone stimulate the vomiting center, which initiates emesis.1
1. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med. 1993;329:

6. CINV Acute (post-treatment) Delayed Anticipatory Breakthrough
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

7. 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

8. Perception vs. Reality: Emetogenic Chemotherapy
Highly Emetogenic Chemotherapy
Moderately Emetogenic Chemotherapy
In an international prospective observational study of 298 patients from 14 oncology practices performed in , 97% of patients received a 5-HT3 receptor antagonist, with 78% receiving a corticosteroid prior to receipt of moderately or highly emetogenic chemotherapy (78% received moderately emetogenic regimens).
Physicians and nurses overestimated the efficacy of antiemetic treatment for the majority of patients.
The greatest discrepancy between predicted and actual nausea and emesis occurred for the delayed period, with physicians and nurses underestimating the incidence of nausea/vomiting by nearly 30%.
Of interest, even with treatment with antiemetics, 35% of patients experienced acute nausea and over 50% experienced delayed nausea.1
1. Grunberg SM, Hansen M, Deuson RR, Mavros P et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer. 2004;100:
Grunberg S. Cancer. 2004;100:

9. 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

10. 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
Emetogenic Potential of Single Antineoplastic Agents
Shown are agents of moderate to high emetic risk. Low emetic risk (Level 2; 10-30% frequency of emesis) and minimal emetic risk (Level 1; <10% frequency of emesis) agents are also detailed in NCCN guidelines v but not shown here.
Frequency of emesis shown are proportions of patients who experience emesis in the absence of effective antiemetic prophylaxis.
1NCCN guidelines v Available at

12. 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:
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

13. 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 (<0.001)
75.4 vs (<0.001)
Poli-bigelli 2003
82.8 vs (<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
vs 56.2
vs 31.2
Yeo 2009
72.1 vs 72.6
75.6 vs 67.4

14. 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 Diemumsch P et al
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 < for the odds ratio for each comparison

15. 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

16. 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 %

17. 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