the physiology of emesis: why do we need combination ... · 2000 85% 75% 2010 5-ht 3 + steroids ......

Richard J. Gralla, MD Albert Einstein College of Medicine

Bronx, New York, United States

The Physiology of Emesis:

Why Do We Need Combination

Strategies to Minimize CINV?

www.prIMEoncology.org

Controlling Chemotherapy-Induced Emesis Progress Over the Past 30 Years: Efficacy

1980

100% -

75% -

50% -

25% -

Cisplatin (highly emetic) AC chemotherapy

5-day complete control:

0% 10%

50% 50%

1990

60% 50%

2000

85% 75%

2010

5-HT3 +

steroids

Added

NK1

AC, anthracycline–cyclophosphamide

Chemotherapy-Induced Nausea and Vomiting (CINV): Impact on Quality of Life

FLIE, Functional Living Index-Emesis

Lindley CM, et al. Qual Life Res. 1992;1(5):331-340; used with permission from Kluwer Academic Publishers ©1992.

70

80

Mean

FL

IE S

co

res

90

100

110

120

130

Patients experiencing CINV Patients without CINV

115

*

85

121 122

Before chemotherapy (day 1) After chemotherapy (day 3)

(N = 122)

*P = .001

Risk Factors for Emesis and Control Major Clinical Factors

• Chemotherapy regimen

• Gender

• Age

• Chronic alcohol intake history

Controlling Emesis Making Progress

• Understanding the clinical problem

• Understanding the physiology and

neuropharmacology

Borison HL, et al. J Clin Pharmacol. 1981;21(8-9 Suppl):23S-29S.

Neuropharmacology of Chemotherapy-Induced Emesis

Neurotransmitters, Antiemetics and Receptors

Acute Emesis: Moderate and High Risk

SEROTONIN

SUBSTANCE P

DOPAMINE

5-HT3

NK1

D2

Setron

NK1 RA

MCP

MCP, metoclopramide

NEURON

(In high

Doses)

Selectivity of Antiemetics Receptor Binding Affinity

Receptor Granisetron Metoclopramide

5-HT3 8.4 6.6

Other 5-HT -- --

Dopamine -- 8.1

Histamine -- --

Opioid -- --

Neurokinin -- --

http://www.its.caltech.edu/~kiowa/science/5HT3/5HT3_Research.html. Lundbeck Institute. CNS Forum: The 5-HT3 Receptor.

Available at: http://www.cnsforum.com/educationalresources/imagebank/receptor_systems_serotonergic/5ht3_struc. Accessed

25 September 2014.

5-HT3 Receptor

5-HT

Binding Affinity of 5-HT3 Receptor Antagonists

1. Wong EH, et al. Br J Pharmacol. 1995;114(4):851-859. 2. van Wijngaarden I, et al. Eur J Pharmacol. 1990;188(6):301-

312. 3. Miller RC, et al. Drug Dev Res. 1993;28(1):87-93.

5-HT3 antagonist: pKi (nM):

Palonosetron1 10.4

Granisetron2 8.4

Ondansetron2 8.1

Dolasetron3 7.6

The Effect of Adding Dexamethasone to 5-HT3 Antagonists on Acute Emesis

Jantunen IT, et al. Eur J Cancer. 1997;33(1):66-74.

P >.2

P >.00001

Emetic reflex

GABA

Histamine

Endorphins

Acetylcholine

Dopamine / D2 RAs

Serotonin / 5-HT3 RAs

Cannabinoids

Neurotransmitters and Antiemetics

Substance P /

NK1 RAs

D2, dopamine; GABA, gamma-aminobutyric acid; NK, neurokinin; Ras, receptor antagonists

Metoclopramide

Haloperidol Dolasetron

Granisetron

Ondansetron

Palonosetron

Tropisetron

Aprepitant

Netupitant

Rolapitant

Neurotransmitter Antagonist Antiemetics: Effects in Emesis Models

1. Andrews PR, et al. Emesis in Anti-Cancer Therapy. Mechanisms & Treatment. London: Chapman & Hall Medical;

1993. 2. Watson JW, et al. Br J Pharmacol. 1995;115(1):84-94. 3. Costall B, et al. Neuropharmacology. 1990;29(5):453-

462. 4. Miner WD, et al. Br J Pharmacol. 1986;88(3):497-499.

Emetic

stimulus

Action site Neurotransmitter receptors

Central Peripheral NK-1 5-HT3 D2

Apomorphine X1 X2 X3

Loperamide X1 X2

Copper

sulfate X1 X2

Ipecac X1 X1 X2 X3 X/-3

Cisplatin X1 X1 X2 X4 X/-3

Baseline PET

Aprepitant 125 mg

PET scan 24 hours post-dose demonstrated >90% NK-1 receptor occupancy following single oral aprepitant 125 mg dose

PET Imaging Under Baseline and Blocked Conditions Following a Single Dose of Rolapitant and Aprepitant

Blocked PET Baseline PET

120 hrs

Rolapitant 200 mg

PET scan 5 days post-dose demonstrated >90% NK-1 receptor occupancy following single rolapitant 200 mg oral dose

24 hrs

Rolapitant 200 mg

Aprepitant 125 mg

11C-GR205171

Blocked PET

NK1 Receptor Antagonists and Brain NK1 Receptors in Humans

Dose n Time % Occupancy

(striatum)

Netupitant1 300 mg 2 96 hours 76%

450 mg 2 96 hours 83%

Aprepitant2 165 mg 3 120 hours 37%-76%

Fosaprepitant2 150 mg 3 120 hours 41%-75%

Rolapitant3 200 mg 2 120 hours >90%

1. Spinelli T, et al. J Clin Pharmacol. 2014;54(1):97-108. 2. Van Laere K, et al. Clin Pharmacol Ther. 2012;92(2):243-250.

3. Poma A, et al. Presented at: 2014 MASCC/ISOO International Symposium on Supportive Care in Cancer; June 26-

28, 2014: Miami, Florida.

Major Antiemetic Classes Therapy: Based on Physiology and Clinical Studies

• Corticosteroids: High value in delayed and acute settings

– Dexamethasone in acute emesis:

Appropriate doses in high-risk and moderate-risk settings have been defined

Single dosing is as good as multiple most settings

– Dexamethasone in acute and delayed emesis:

Documentation of safety

• Serotonin antagonists: Cornerstone of treatment

– Remain the agents of choice in broad antiemetic applications

– Palonosetron is the preferred agent in several settings as recommended by evidence based guideline groups

• NK1 antagonists: Important additive agent

– Benefits in both acute and delayed emesis

• In antiemetic studies, nausea is always reported in as exceeding vomiting, in incidence and duration

• There is a strong correlation between nausea and vomiting (r>0.9)

– Failure to control vomiting is rarely associated with control of nausea

Nausea Leading to Vomiting: Observations and Hypothesis

Rolapitant: “HEC1 Trial”

Efficacy variable

HEC1: Overall 5-day control

Rolapitant**

(N = 264)

rate (%)

Control***

(N = 262)

rate (%) P value

No emesis1 75.4 59.2 <.001

No nausea2 49.6 39.3 .018

Complete protection3 64.0 50.4 .002

A randomized trial in 526 patients receiving highly emetic chemotherapy*

1No emesis: No vomiting, retching, or dry heaves 2No nausea: Maximum VAS <5 mm on the scale of 0 to 100 mm 3Complete protection: No emesis, no rescue medication, and maximum nausea VAS <25 mm

*Cisplatin ≥60 mg / M2 or Hesketh level ≥4

**Rolapitant arm: Rolapitant 200 mg po + granisetron + dexamethasone (Rolapitant is an investigational agent)

***Control arm: Placebo + granisetron + dexamethasone

Rapaport B, et al. J Clin Oncol. 2014;32(5s): Abstract 9638; Rapoport B, et al. Lancet Oncol. 2015 [Epub in Press]

• In antiemetic studies, nausea is always reported in as exceeding vomiting, in incidence and duration

• There is a strong correlation between nausea and vomiting (r>0.9)

– Failure to control vomiting is rarely associated with control of nausea


Hypotheses: 1. Nausea involves more neurotransmitters than does vomiting

• Common clinical progression: Anorexia > Nausea > Vomiting

2. The anti-vomiting effects of antiemetics work by reducing nausea

• Antiemetics do not allow a nausea stimulus to propagate and

to reach a vomiting threshold

3. Both of the above

Rat

Shrew

Ferret

Human

Dog

Nausea Leading to Vomiting – Threshold

Variation and range among individuals,

as with other physiologic functions:

Renal, cardiac, etc

Males

Females

Nausea Leading to Vomiting – Threshold: Humans

Relative threshold level similar no

matter what the stimulus

Not surprising that those with motion-

sickness are more difficult to control

when receiving chemotherapy…and

more difficult to control nausea in

women with either chemotherapy or

postoperatively

Humans


Perceptible nausea level

Vomiting threshold

Physiologic events: Gastric stasis,

anorexia…

These levels or

thresholds may

change throughout

life or health

Nausea

Stimulus

Humans



Vomiting threshold

Very

strong

Weak

Moderate

TIME

Humans


Vomiting threshold

TIME

EFFECT OF

ANTIEMETICS

Patient #1

Patient #2


• There are several implications if this hypothesis is correct:

– The hypothesis illustrates why the control of nausea is consistently less than the control of vomiting

– Available antiemetic agents decrease nausea, as well as vomiting

– It is appropriate to have the control of nausea as the primary endpoint in major antiemetic trials

– Nausea can be accurately and reproducibly measured as a “PRO”


Progress in antiemetic control reflects the use of evidence from both clinical and basic studies

Translational research in this area has gone from the clinic to the laboratory and in reverse

Current treatment is based on a sound understanding of the physiology and neuropharmacology of this problem

Future research needs to build on the increasing understanding of the physiology of nausea and vomiting

the physiology of emesis: why do we need combination ... · 2000 85% 75% 2010 5-ht 3 + steroids ......

Documents