Aprepitant: A new Drug for Chemotherapy Induced Nausea and Vomiting

Girish C

Dept. of Pharmacology,

JIPMER, Pondicherry, INDIA

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

Introduction

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

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

Types of CINV

Vomiting Centre (medulla)

Cerebral cortex

Anticipatory emesisSmellSight

Thought

Pharynx & GIT

Chemo & radio therapy

Chemoreceptor Trigger Zone

(CTZ)(Outside BBB)

Cancer chemotherapy

Ach, 5 HT Histamine & Substance P

5 HT & Substance P

Dopamine

5 HT, substance P

Pathophysiology of CINV

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%)

Ineffectiveness in delayed emesis

Not effective in all patients

Ineffective once symptoms develop

Limitations

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

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

Empirical formula: C23H21F7N4O3

Chemistry

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

o Hesketh PJ et al.,Poli-Bigelli S et al.,

o Multicenter, randomized, double blind placebo controlled study

o Chemotherapy naïve patients receiving highly emetogenic chemotherapy including Cisplatin≥ 70mg/m2

Dexa 8mg b d

Days1 2 3 4 5 6 7

Ondan 32mg iv

Dexa 20 mg oral

Days1 2 3 4 5 6 7

Apre 125mg

Ondan 32mg iv

Dexa 12 mg oral

Dexa 8mg

Apre 80mg

Dose Schedule

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. 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.

Thank YouThank You