1. Aprepitant: A new Drug for Chemotherapy Induced Nausea and Vomiting
Girish C
Dept. of Pharmacology,
JIPMER, Pondicherry, INDIA

2. Introduction
Nausea and vomiting -- devastating side effects of antineoplastic agents
Uncontrolled emesis affect quality of life and impair compliance with treatment
About % patients experience emesis & 10-44% have anticipatory emesis
The potential for Chemotherapy induced Nausea and Vomiting (CINV) is influenced by
Emetogenic potential of antineoplastic agents
Patient related factors

3. Emetogenic Potential of Antineoplastic agents
Navari RM. Pathogenesis-based treatment of chemotherapy – induced nausea and vomiting – Two new agents. J Support Oncol 2003;1:89-103

4. Patient Related Risk Factors
Navari RM. Pathogenesis-based treatment of chemotherapy – induced nausea and vomiting – Two new agents. J Support Oncol 2003;1:89-103

5. Types of CINV
Acute CINV: Nausea and vomiting with in the first 24 hrs of chemotherapy
Delayed CINV: After 24 hrs lasting up to 5 days
Anticipatory CINV: After a negative past experience with chemotherapy
Breakthrough CINV: Occurs despite patient being treated with preventive therapy
Refractory CINV: Occur during subsequent cycles of chemotherapy when antiemetic prophylaxis has failed in earlier cycles

6. Pathophysiology of CINV
Cerebral cortex
Cancer chemotherapy
Smell
Sight
Thought
Anticipatory emesis
Chemoreceptor Trigger Zone (CTZ)
Vomiting Centre (medulla)
Ach, 5 HT Histamine & Substance P
(Outside BBB)
Dopamine
5 HT, substance P
Chemo & radio therapy
Pharynx & GIT
5 HT & Substance P

7. Approaches in the management of CINV
Emetic center
Serotonin
Dopamine
Substance P
Endorphins
Acetylcholine
Histamine

8. Dopamine receptor antagonists( Metoclopramide, Phenothiazines, butyrophenones)
1990- First selective 5 -HT3 receptor antagonist introduced (Ondansetron )
Addition of dexamethasone further improved these symptoms ( Acute emesis up to 60-70%)

9. Limitations Ineffectiveness in delayed emesis
Not effective in all patients
Ineffective once symptoms develop

10. Focus on New Targets…
Substance P - belongs to tachykinin family of peptides
Neurokinin A &B are other members
Present in CNS( neurotransmitter), GIT( transmitter in enteric nervous system & act as local hormone)
Implicated in behavior, anxiety, depression, nausea& vomitting
Tachykinins act through Neurokinin type 1(NK1) , NK2 & NK3 receptor

11. Substance P is the major ligand for NK1
NK1 receptors are dense in NTS, DMVN and vagal afferent nerve fibers in GIT
Blockers of NK1 receptor lessen emesis in experimental studies
Aprepitant is first drug of NK1 receptor antagonists

12. Aprepitant
Non peptide, selective, Neurokinin type 1 (NK 1) receptors antagonist
Block substance P from binding to NK1 receptor
Broader spectrum and activity in delayed emesis (In Preclinical studies)
Augment the antiemetic activity of 5HT3 receptor antagonists and dexamethasone
Inhibit both acute and delayed CINV

13. Empirical formula: C23H21F7N4O3
Chemistry
Empirical formula: C23H21F7N4O3
5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one

14. Pharmacokinetics

15. Orally active
Bioavailability of 60-65%... unaffected by food
Tmax -- after 4 hrs of oral dose
Volume of distribution -70 L
95% bound to plasma proteins
Crosses BBB & placental barrier
Metabolism in liver (CYP3A4)
Excreted in urine (50%) and in feces(50%)

16. Drug Interactions

17. A substrate, moderate inducer and moderate inhibitor of CYP3A4
Induces CYP2C9
Pimozide, terfenadine, astemizole and cisapride should not be used concurrently with aprepitant
Docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine
Interact with warfarin, dexamethasone, methylprednisolone, oral contraceptives

18. Adverse Effects
Asthenia(17.8%), hiccups(10.85%), diarrhoea(10.3%), heartburn(9.5%), dizziness, elevation in LFT values
Case reports of angioedema, urticaria, Stevens- Johnson syndrome

19. Indications and Dose
FDA approved on March 2003 for prevention of acute and delayed CINV with single or repeated courses of highly emetogeneic chemotherapy
125 mg on day 1 (before chemotherapy) and then 80mg on days 2 and 3(after chemotherapy)
Should be given with a 5HT3 antagonist and dexamethsone
Dose of dexamethasone should be reduced by 50%

20. Clinical Trials Hesketh PJ et al.,Poli-Bigelli S et al.,
Multicenter, randomized, double blind placebo controlled study
Chemotherapy naïve patients receiving highly emetogenic chemotherapy including Cisplatin≥ 70mg/m2

21. Dose Schedule Ondan 32mg iv Dexa 20 mg oral Apre 125mg Ondan 32mg iv
Dexa 8mg b d
Days
Ondan 32mg iv
Dexa 20 mg oral
Days
Apre 125mg
Ondan 32mg iv
Dexa 12 mg oral
Dexa 8mg
Apre 80mg

22. Summary of the main results from the phase III aprepitant trials
(Complete response= No emesis and no rescue therapy)
Thein H Oo, Hesketh PJ. Drug Insight: new antiemetics in the management of chemotherapy-induced nausea and vomiting .Nature Clinical Practice Oncology ,2005; 2 :

23. National Comprehensive Cancer Network(NCCN) Guidelines
High Emetic Risk Chemotherapy- Emesis prevention

24. Moderate Emetic Risk Chemotherapy- Emesis prevention

25. Patient Counseling Dosing schedule should be explained
Should not be taken as monotherapy
If breakthrough CINV occurs, take lorazepam or prochlorperazine
Herbal drug interactions
Alternative contraceptive methods for women on oral contraceptives

26. Other NK1 receptor Antagonists…
Vafopitant
CP-122,721
CJ-11,794
L-758,298

27. Future Directions Use with other antiemetic combinations
Use in multiday chemotherapy, in stem- cell transplantation and pediatric patients
Use in other moderately emetogenic settings
Results of trials with other NK1 antagonists

28. Summary Aprepitant – a clear-cut therapeutic advance
Good safety profile
Effective in Breast cancer patients (cyclophosphamide/anthracycline based chemotherapy)
Potential for drug interactions
High cost of the drug

29. References:
1. Kris MG. Why Do We Need Another Antiemetic? Just Ask. Journal of Clinical Oncology, 2003; 21:
2. Tramèr MR. Treatment of postoperative nausea and vomiting .Better data, improved control have been achieved during recent years. BMJ 2003;327:762–3.
3. Rittenberg CN. A new class of antiemetic agents on the horizon. Clinical journal of Oncol Nursing 2002;6:103-4.
4. Huskey SW, Dean BJ, Bakhtiar R, Sanchez RI, Tattersall FD, Rycroft W,et al.,Brain penetration of aprepitant, a substance p receptor antagonist, in ferrets ,Drug Metabol Dispos 2003 ;31:785–91.

30. 5. Saito R, Takano Y, Kamiya H
5. Saito R, Takano Y, Kamiya H. Roles of substance P an NK1 receptor in brain stem in the development of emesis. J Pharmacol Sci 2003; 91:
6. Navari RM. Pathogenesis-based treatment of chemotherapy – induced nausea and vomiting – Two new agents. J Support Oncol 2003;1:
7. Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 2002; 3(Suppl 11):18-24.
8. Sanger GJ. Neurokinin NK1 and NK3 receptors as targets for drugs for to treat gastrointestinal motility disorders and pain. BJP 2004; 141:

31. Thank You