Transcript Partial agonist

니코틴의존의 새로운 약물치료
가톨릭대학교 성가병원
신경정신과 금연클리닉
김
대
진
금연 성공 ‘의지’
만으론 부족하다
- 한겨례. 2005. 5. 3. -
니코틴 의존에 관한 이해
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중독
약물남용/의존
갈망
뇌보상회로
NEUROBIOLOGY
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Why Smoke?
Addiction
Dopamine
VTA, nAcc
Withdrawal Symptoms
Why Do People Smoke?
Addiction – Habitual psychological and physiological dependence on
substance or practice which is beyond voluntary control
– Stedman’s Medical Dictionary
 Since at least the 1988 US Surgeon General’s Report1
– Addiction defined as compulsive use despite damage to the individual or
society and drug-seeking behavior can take precedence over important
priorities
– Addiction persists despite a desire to quit or even repeated attempts to
quit
 Most people smoke primarily because they are addicted to nicotine2
 There is a clear link between smoking, nicotinic receptors, and
addiction2
1. Centers for Disease Control and Prevention. The Health Consequences of Smoking: Nicotine Addiction; A
Report of the Surgeon General. Washington DC: US Department of Health and Human Services; 1988.
2. Jarvis MJ. BMJ. 2004;328:277-279.
뇌보상회로
 뇌 안에 존재하는 긍정적인 보상 또는 강화시스템
 양성강화시스템
– 뇌의 자극을 통해 행동의 반복을 유발
– 먹는 것, 성행위 등 생존과 종족 보존을 위한 기본적인 생
물학적 기능들은 반복적으로 일어나게 하기 위한 것
– 일생을 통하여 이들 중추들을 자극하는 경험을 배우게 됨
 그러나 인위적으로 이들 뇌보상회로를 활성화시킬 수
있음
Natural Rewards and then…
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Food
Water
Sex
Nurturing
NA
VTA
PFC prefrontal cortex
NA nucleus accumbens
VTA ventral tegmental area
A amygdala
C cingulate gyrus
H hippocampus
Nicotine Addiction: Reinforcin
g Behavior
b2 b2
a4 b2 a4
a4b2 nicotinic
ACh receptors
Dopamine
nicotine
GABA
GLU
 Nicotine activates nAChRs on Dopamine neurons in the VTA
 Enhanced DA release in the n. accumbens (‘reward system”)
Rollema et al (2007) TiPS 28(7): 316-325
Nicotine Receptor
Initial smoking
= activated
= sensitive
= desensitised
Nicotine Receptor
Smoking upregulation
= activated
= sensitive
= desensitised
TOLERANCE
Short term:
Related to the status of the receptor
Long term:
Related to number of receptors
Smoker
Non Smoker
C-11
Nicotine
Nordberg Pers com
Nicotine Receptor
Under withdrawal
= activated
= sensitive
= desensitised
STRIATAL DOPAMINE RELEASE FOLLOWING NICOTINE
ADMINISTRATION
Non-smokers
Smokers
nicotine
BP reduction in the striatum
Enhanced dopamine release in smokers
Takahashi et al Int J Neuropsychoparmacol 2007
Nicotine dependence and dopamine release
FTND
Positive correlation between
FTND score and BP reduction
The more you dependent, the more you release dopamine
Takahashi et al Int J Neuropsychoparmacol 2007
Rationale: a4b2 nAChR partial agonists
for smoking cessation
Theoretical paper by Jed Rose & Edward Levin*:
“Improved efficacy by combining nicotine (an
agonist) with mecamylamine (an antagonist)”
* Rose and Levin (1991) Concurrent Agonist-Antagonist
Administration for the Analysis and Treatment of Drug
Dependence. Pharmacol Biochem Behav 41: 291-226
Hypothetical effects of smoking without and
with NRT on mesolimbic DA release
Response
to nicotine
Smoking
= cigarette smoked
NRT + smoking
Time
Rollema et al (2007) TiPS 28(7): 316-325
Rationale: a4b2 nAChR partial agonists
for smoking cessation
1992: Dr. Jim Heym (Pfizer Neuroscience)
Instead of nicotine + mecamylamine, better if:
1. Agonist and antagonist properties can be
combined in 1 drug, i.e. a partial agonist
2. Such a drug is selective for the receptor that
mediates addictive effects of nicotine, i.e. a4b2
Therefore: design a a4b2 selective partial agonist
Hypothetical effects on mesolimbic DA
release of smoking with NRT or with
Nicotinic Partial Agonist
Response
to nicotine
Smoking
= cigarette smoked
NRT + smoking
Partial agonist + smoking
Time
Rollema et al (2007) TiPS 28(7): 316-325
Agonist and Antagonist actions
of a a4b2 nAChR Partial Agonist
Smoking
No Partial Ag
No Smoking
Partial Ag
Smoking
+ Partial Ag
Nicotine
Nicotine
Part Ag
Part ag
Agonist
Partial Agonist
Antagonist
100%
50%
50%
a4b2 nAChR
Response
Potential to relieve
craving and withdrawal
when quitting
Potential to block
reinforcing effects
when smoking
Dual action of a partial agonist
Functional activity and efficacy:
Agonist action
Agonist Effect
100%
50%
Full agonist
(nicotine)
Partial agonists
with 50% efficacy
Relieves craving and withdrawal
0%
Dose, exposure
Rollema et al (2007) TiPS 28(7): 316-325
Functional activity and
efficacy: Antagonist action
Antagonist effect
100%
Nicotine effect
Nicotine +
potent 50% partial agonist
Nicotine +
weak 50% partial agonist
Blocks reinforcement
50%
0%
Dose, exposure
Rollema et al (2007) TiPS 28(7): 316-325
Synthesis: Clues from Nature
Tobacco plant
Golden Chain
Nicotine
Opium poppy
Morphine
Cytisine
OH
H
N
H
N
O
N
N
N
H
N
O
OH
HN
Varenicline synthesized Feb 1997
NH
N
N
Varenicline
Coe et al (2005) J Med Chem 48: 3474-3477
Properties 1 - Binding to the receptor: Affinity
In vitro receptor binding: displacement of labeled ligand
Neurotransmitter or drug:
Acetylcholine, nicotine, varenicline
compound
Receptor, transporter:
a4b2 nAChR
radiolabeled ligand
Measure concentration of free radio-label: affinity
High Binding Affinity = Low Ki (in nM)
Properties 2 - Effect on the receptor: Activity
In vitro electrophysiology (current by patch clamp)
Neurotransmitter or drug:
Acetylcholine, nicotine, varenicline
Receptor, transporter:
a4b2 nAChR
Depolarisation: effect
Measure the current evoked by drug application:
EC50 = functional potency
Emax (max effect as % of nicotine) = functional efficacy
Partial agonist activity in vitro at a4b2
nAChRs expressed in HEK cells
I, (pA)
drug on
0
Varenicline 0.3 µM
-200
Varenicline 1.0 µM
-400
Varenicline 10 µM
Varenicline 3.0 µM
-600
45% partial agonist
EC50= 3.1 mM
Nicotine 10 µM
-800
0
2
4
6
8
10
Time (s)
(VH = -60 mV, 2 sec. agonist application)
Rollema et al (2007) Neuropharmacology 52: 985-994
Antagonist activity in vitro at
a4b2 nAChRs expressed in HEK cells
Varenicline 10 mM
Varenicline 1.0 mM
Varenicline 0.1 mM
200
Nicotine 10 mM
Current (pA)
0
-200
55% antagonist
IC50= 0.8 mM
-400
-600
-800
-1000
0
5
10
15
20
Time (sec)
Rollema et al (2007) Neuropharmacology 52: 985-994
25
Properties 3 – Effect on DA: Function and Potency
In vivo microdialysis in rat nucleus accumbens
Partial agonist and antagonist effects
on dopamine release in rat nucleus
accumbens
% of Basal ± SEM
Dopamine Release in N. Accumbens
200
Nicotine 0.32 mg/kg sc
175
Varenicline 1 mg/kg po
+ Nicotine 0.32 mg/kg sc
150
Varenicline 1 mg/kg po
125
100
Varenicline 1
mg/kg po
75
-180
-120
-60
Nicotine 0.32 mg/kg
0
60
120
180
240
Time (minutes)
Coe et al (2005) J Med Chem 48: 3474-3477
300
360
Properties 4 – Behavior: Animal model of Addiction
Nicotine Self-Administration in rats
Drug
reservoir
Sound-proof enclosure
Computerized data
collection and operant
controller
Swivel
Operant chamber
Valve
Syringe pump
assembly
Tether
S.C. saddle
Nose poke
holes
Lights for
reinforcement response
Operant system for intravenous self-administration
Operant system for intravenous
of drugs
of drugs self-administration
in mice.
Varenicline has the desired properties:
 Potent binding affinity at a4b2 nAChRs
 Highly selective for a4b2 nAChRs
 40-60% partial agonist efficacy at a4b2 nAChRs
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in vitro (HEK cells, electrophysiology)
 in vitro ([3H]-DA release)
 ex vivo (DA turnover)
 in vivo (DA release)
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Minimal or no abuse liability
 Excellent oral bioavailability
“Drug-like” pharmacokinetic properties
Absorption
 Good membrane penetration, highly absorbed
 Rapid absorption: median Tmax = 3 h
 Distribution
 Low protein binding (fu  0.8) and moderate VDistribution (1.9 L/kg)
 Not a substrate for the P-glycoprotein efflux transporter
 Metabolism
 Not metabolized: excreted >90% as unchanged drug in the urine
 Does not inhibit cytochrome P450 enzymes
 Excretion
 Renal clearance (mainly passive diffusion): 2.4 mL/min/kg
 Long half life: T1/2 ~24 hr in man
Addictive Nature of Nicotine
 The addictive characteristics of nicotine are believed
to be a result of its rapid, intense and short-acting
effects on dopamine release in the brain
– When inhaled, nicotine reaches the brain within 10 seconds
– Nicotine's half-life is approximately 2 hours
 Similar to addictions associated with cocaine,
amphetamines and opiates, nicotine addiction is a
chronic, relapsing medical condition and warrants
clinical intervention
– Nicotine, cocaine, amphetamines and morphine act on different
areas in the dopamine reward system that encompasses theme
so limbic portion of the bra in.
– Among users of alcohol, tobacco, cannabis, and cocaine,
tobacco users were more likely to be nicotine dependent (28%)
than alcohol (5.2%), cannabis (8.2%) or cocaine (11.6%) users
1. CDC. Surgeon General's Report. The Health Consequences of Smoking. 2004. 2. Foulds J.lntJ Clin Pract.
2006;60:571-576. 3. Fiore MC et al. U.S. DHHS. U.S. Public Health Service, 2000. 4. Changeux JP et al. Brain
Research Reviews. 1998;26:1 98-21 6. 5. Kandel D et al. Drug Alcohol Depend. 1997:44:11-29. 18
Varenicline - a selective a4b2
receptor partial agonist
Partial agonist
 Binds with high affinity to the
a4b2 receptor, only partially
stimulating dopamine release1
 Provides relief from craving
and withdrawal symptoms1-3
Antagonist
 Prevents stimulation of the
receptor by nicotine1,4
 This reduces the pleasurable
effects of smoking and
potentially the risk of full relapse
after a temporary lapse1-4
1. Coe JW. J Med Chem 2005; 48:3474-3477. 2. Gonzales D et al. JAMA 2006;296:47-55. 3. Jorenby DE et al. JAMA 2006; 296:56-63. 4. Foulds J. Int J Clin Pract 2006; 60:571-576.
Varenicline - the evidence
 Meta-analysis1 of randomised placebo controlled
trials shows that varenicline is more effective than
– Placebo OR = 3.22; (95% CI: 2.43-4.27)
– Bupropion OR = 1.56 (95% CI: 1.19-2.06)
 Indirect comparison2 shows that it is better than
NRT
(1) Cahill, K., L.F. Stead, and T. Lancaster, Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst
Rev, 2007 (2) Wu, P., et al., Effectiveness of smoking cessation therapies: a systematic review and meta-analysis. BMC Public
Health, 2006. 6
Subjective effects
 Varenicline:
– reduced patient ratings of urges to smoke compared
with placebo and bupropion
– reduced ratings of mood disturbance compared with
placebo
– reduced patient ratings of satisfaction and reward
from their cigarette in those who smoked a cigarette
after the quit date, compared with placebo and
bupropion
West, R., et al., Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding
effects of smoking during a quit attempt. Psychopharmacology (Berl), 2007
Prescribing information
 Contra-indications
– Hypersensitivity to varenicline or excipients
 Cautions
– Pregnancy – not recommended, breast feeding risk/benefit, age <18 – not recommended (safety not
established), renal impairment – reduce to 1mg/day,
psychiatric illness (secondary to cessation)
 Adverse events
– Nausea – experienced by approximately a third of people
that use it; mostly mild; dissipates over time
– Sleep disturbance (most likely to be an abstinence effect)
– Recent concern over relationship with suicidal ideation
(most likely to be an effect of stopping smoking)
CHAMPIX dosing
instructions1
1. CHAMPIX (varenicline tartrate) Approved Product Information. Pfizer Australia Pty Ltd..
The future of treatment
 More effective use of existing treatments
–
–
–
–
combinations
pre-treatment
longer term use if required
wider access
 Better treatments
– novel medications
– cheaper medications
– more comprehensive behavioural treatments
 A realistic goal
– 25% of quit attempts that would have failed, lasting
for at least 6 months
The old way
Cold Turkey (aged 22)
Self-help book
•Smokers don’t
know of or see the
need for treatment
Hypnosis
•Physicians not
engaged
NRT from the pharmacy
Problem?
M.I. (aged 50)
Sees Physician (ABC)
Meds PLUS support
QUITS (age 55)
Adapted from: John Hughes
A better way
Cold Turkey (aged 22)
•Physicians engaged
Sees Physician (ABC)
(Meds + Support)
•Evidence-based
treatments actively
promoted
Relapses
Sees Physician (ABC)
(Meds + Support)
QUITS (age 30)
Adapted from: John Hughes
Summary
Intervention
brief advice
support
NNT
40
telephone
individual
group
30
25
20
nicotine replacement therapy
bupropion
nortriptyline
varenicline
17
13
11
7
pharmacotherapy
Comparative studies:
abstinence data
Odds Ratio (95% CI)
30
20
2.82
1.56
1.80
(2.06, 3.86; P<0.0001)
(1.19, 2.06; P<0.0013)
(1.29, 2.51; P<0.0004)
22.5%
15.7%
9.4%
10
0
Varenicline Bupropion
1 mg bid 150 mg bid
(n=692)
(n=669)
Placebo
(n=684)
Responders (%)
CA rate (%)
40
V vs P
V vs B
B vs P
50
45
40
35
30
25
20
15
10
5
0
Varenicline
Bupropion
Placebo
12 16 20 24 28 32 36 40 44 48 52
Week
Gonzales DH, Rennard SI, Billing CB, et al. A pooled analysis of varenicline: an α4β2 nicotinic receptor partial agonist vs. bupropion for smoking
cessation. SRNT Paper sessions PA9-2, PA9-3, 2006.
Outcomes of Clinical trialVarenicline (1)
 1mg of varenicline twice a day vs. 150mg of
bupropion twice a day for 12 weeks.
Jorenby et al. JAMA 2006
Outcomes of Clinical trialVarenicline (2)
 12 weeks open label, following 12 weeks double blind
placebo controlled among the abstainers.
Tonstad et al. JAMA 2006
Frequent adverse events
Jorenby et al. JAMA 2006
Meta-analysis data about
varenicline
3.22 [2.43, 4.27]
1.66 [1.28, 2.16]
Phase III results in Korea (1)
CAR(Weeks 9–12)
OR[95% CI] = 3.22[1.89, 5.47]; p<0.0001
Placebo
(N=124)
80
59.5
60
40
32.3
Varenicline 1
mg BID
(N=126)
20
0
CAR(Weeks 9–24)
100
Response Rate (%)
Response Rate (%)
100
OR[95%CI]=3.38[1.91, 5.99]; p<0.0001
Placebo
(N=124)
80
60
46.8
40
21.8
20
0
Varenicline
1 mg BID
(N=126)
Most frequent† adverse
events
Varenicline
(N=126)
n (%)
Placebo
(N=124)
n (%)
Total all-causality AEs
109 (86.5)
98 (79)
Total treatment-related AEs
96 (76.2)
73 (58.9)
Nausea
54 (42.9)
14 (11.3)
Insomnia
12 (9.5)
9 (7.3)
Abnormal dreams
7 (5.6)
1 (0.8)
Fatigue
8 (6.3)
6 (4.8)
Adverse events
†Occurring
in ≥5% of subjects in the varenicline treatment group; AEs, adverse events
A Simulation of Plasma Concentration Throughout
the Day in Relation to Psychoactive Effect
To Quit Smoking is Easy?
All Smoker
~70%
Want to quit1
~30%
Try to quit2
~2–3%
Succeed to quit3
1. Bridgwood et al. General Household Survey 1998; 2. West. Getting serious about stopping smoking 1997; 3.
Arnsten, Prim Psychiatry 1996.
Nicotine Addiction: A Chronic
Relapsing Medical Condition
 True drug addiction1
 Requires long-term clinical intervention, as do other addictive
disorders
– Failure to appreciate the chronic nature of nicotine addiction
may2
 Impair clinicians’ motivation to treat tobacco dependence long-term
 Impede acceptance that condition is comparable to diabetes,
hypertension, or hyperlipidemia, and requires counseling, support, and
appropriate pharmacotherapy
 Relapse is
– Common1,2
– The nature of addiction, not the failure of the individual3
 Long-term smoking abstinence in those who try to quit unaided† = 3%–5%
 Most relapse within the first 8 days
1. Fiore MC, Bailey WC, Cohen SJ, et al. Clinical Practice Guideline: Treating Tobacco Use and Dependence.
US Department of Health and Human Services. Public Health Service; June 2000. Available at:
www.surgeongeneral.gov/tobacco/default.htm. 2. Jarvis MJ. Why people smoke. BMJ. 2004;328:277-279.
Multiple Quit Attempts
May Be Necessary
 More than 70% of US smokers have attempted to quit1
– Approximately 46% try to quit each year
– Less than 5% who try to quit are abstinent 1 year later
– Similar percentages in countries with established tobacco control
programs (eg, Australia, Canada, UK)2
 30% to 50% try to quit; <5% achieve long-term abstinence
 Some smokers succeed after making several attempts3
– Past failure does not prevent future success
– Length of prior abstinence is related to quitting success
1. Fiore MC, et al. US Department of Health and Human Services. Public Health Service. June 2000. 2. Foulds J,
et al. Expert Opin Emerg Drugs. 2004;9:39–53. 3. Grandes G, et al. Br J Gen Pract. 2003;53:101–107.
Increased plasma BDNF levels after
unaided smoking cessation