aprepitant: a new drug for chemotherapy induced nausea and vomiting girish c dept. of pharmacology,...
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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.
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