Transcript Document

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 & 1044% 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
Chemoreceptor
Trigger Zone
(CTZ)
(Outside BBB)
Dopamine
5 HT, substance P
Smell
Sight
Thought
Anticipatory emesis
Vomiting Centre
(medulla)
Ach, 5 HT Histamine &
Substance P
Chemo & radio therapy
Pharynx & GIT
5 HT &
Substance P
Approaches in the management of CINV
Serotonin
Substance P
Endorphins
Dopamine
Emetic center
Histamine
Acetylcholine
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
Chemistry
Empirical formula: C23H21F7N4O3
5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4fluorophenyl)-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, StevensJohnson 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
Dose Schedule
Ondan 32mg iv
Apre 20
125mg
Dexa
mg oral
Ondan 32mg iv
Apre
80mg
Dexa 12 mg oral
Days 1
2
3
4
5
6
7
Days 1
2
3
Dexa 8mg b d
4
5
6
7
Dexa 8mg
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 You