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

Introduction Nausea and vomiting -- devastating side effects of antineoplastic agents Uncontrolled emesis affect quality of life and impair compliance with treatment About 70- 80% 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

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

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

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

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

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

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%)

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

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

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

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

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

Pharmacokinetics

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%)

Drug Interactions

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

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

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%

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

Dose Schedule Ondan 32mg iv Dexa 20 mg oral Apre 125mg Ondan 32mg iv Dexa 8mg b d Days 1 2 3 4 5 6 7 Ondan 32mg iv Dexa 20 mg oral Days 1 2 3 4 5 6 7 Apre 125mg Ondan 32mg iv Dexa 12 mg oral Dexa 8mg Apre 80mg

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 :196-201

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

Moderate Emetic Risk Chemotherapy- Emesis prevention

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

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

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

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

References: 1. Kris MG. Why Do We Need Another Antiemetic? Just Ask. Journal of Clinical Oncology, 2003; 21:4077-80. 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.

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: 87-94. 6. Navari RM. Pathogenesis-based treatment of chemotherapy – induced nausea and vomiting – Two new agents. J Support Oncol 2003;1:89-103. 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; 141:1303-1312.

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