ZIPRASIDONE

1
ZIPRASIDONE
O

HCl
N
H
N
Discovery
goals
CI
N
l
V
ery
potent
5HT
antagonism
2A
N
l
P
otent
D
antagonism
S
2
l
High
5HT
/D
receptor
affinity
ratio
2A
2
l
Relatively
modest
a
adrenergic
1
negligible
H1 affinity
and
muscarinic
affinity
J
Med
Chem
1996
39
143148
2
ZIPRASIDONE COMPARATIVE RECEPTOR PROFILE
Zip, ziprasidone RIS, risperidone OLZ,
olanzapineQTP, quetiapine SER, sertindole
CLOZ, clozapine
3
SEROTONIN RECEPTOR AFFINITIESRELATIVE TO D2
10
Ziprasidone

Olanzapine

Risperidone
i
K

2
D

o
t

e
v
i
t
1
a
l
e
r

y
t
i
n
i
f
f
A
0.1
5HT
5HT
5HT
5HT
2A
1A
1D
2C
Bars above the line represent receptor affinities
greater than that for the D
receptor
2
Data
on
file,
Pfizer
Inc
4
PET STUDIES METHODOLOGY
l
Objectives
were
to
determine

5HT
and
D
receptor
occupancy
by
ziprasidone
2
2

the
relationship
between
drug
concentration
and
receptor
occupancy
l
Methodology

5HT
PET
using

F-setoperone
(
n
8)
18
2

D
PET
using

C-raclopride
(
n
7)
11
2
l
Subjects

healthy
men
(1845
years)
l
Dose

single
oral
40
mg
5
5HT2 AND D2 RECEPTOR OCCUPANCY
100
90
80
y
c
n
70
a
p
u
c
60
c
o

t
50
n
e
c
40
r
e
P
5HT
model fit
30
2
5HT
raw data
2
20
D
model fit
2
D
raw data
2
10
0
20
0
40
60
80
100
120
Serum ziprasidone concentration (ng/ml)
JPET 1996279(2)939947 Psychopharmacol
1996124141147
6
INHIBITION OF 5HT AND NOREPINEPHRINEREUPTAKE
INTO BRAIN SYNAPTOSOMES
0.04

)
M
n
5HT reuptake inhibition
(

i

NE reuptake inhibition
K
/
0.03
1


y
c
n
e
t
o
p
0.02

g
n
i
k
c
o
l
b

0.01
e
k
a
t
p
U
0.00
Amitriptyline
Imipramine
Ziprasidone
Olanzapine
Risperidone
Data
on
file,
Pfizer
Inc
7
Neurocognitive dysfunction treatment with
atypical antipsychotics

• Atypical antipsychotics as a group appear to be
  superior to conventional neuroleptics with regard
  to cognitive dysfunction
• The variation in pharmacological properties
  between the atypical antipsychotics may have
  important clinical consequences, including
  selective effects on cognition

Meltzer McGurk (1999) Keefe et al (1999)
8
Cognition
Working memory
Executive function
Motor functioning
Visual learning memory
Verbal fluency
9
Effect of Antipsychotics on CognitionTests and
Results
Improvement No Improvement -
Indeterminate
10
Dopamine release in rat prefrontal
cortexTimeresponse curves
400
Dopamine release ( of basal)

Ziprasidone
Clozapine
Olanzapine




300








200
100
Vehicle or Way
Drug
Vehicle or Way
Drug
Vehicle or Way
Drug
0
-120
0
120
240
360
-120
0
120
240
360
-120
0
120
240
360
Vehicle drug
Time (minutes)
WAY-100,635 drug
Watsky et al (1999)
plt0.05, plt0.01 vs dopamine
11
Pharmacology of body weight gain
Serotonin 5-HT1A, B, D, E 5-HT2C, others?
Histamine H1
Dopamine D2
Prolactin
Noradrenaline a1, a2, b
5-HT/NA uptake
Neuromedins
Neuropeptide Y
Cholecystokinin
Opioids Dynorphin, enkephalin
Somatostatin
Galanin
Leptin
Orexins
CRH
MCH
Central control of body weight
12
Ziprasidone receptor profileWhy no weight gain?

• Potent 5-HT2C antagonist
• Moderate a1 antagonist
• Weak H1 antagonist
• Full 5-HT1A agonist
• Moderate 5-HT/NA uptake inhibition

5-HT2A
D2
5-HT1A
5-HT1D
H1
?1
5-HT2C
Data on file, Pfizer
13
ORAL ZIPRASIDONE PHARMACOKINETICS
l
T
68
hours
max
l
Plasma
half
-life510
hours
l
Steady
state
in
13
days
l
Dose
proportionality
over
the
range
40160
mg/day
l
Absolute
bioavailability
with
food60
l
No
dosage
adjustment
in
elderly
,
in
mild/moderate
renal
and
hepatic
impairment
or
for
gender
l
Clinically
inactive
metabolites
(lt1
activity
at
5HT
,
D
,
D
,
D
)
2A
2
3
4
Data
on
file,
Pfizer
Inc
14
Pharmacokinetics of ziprasidone IM Mean
ziprasidone serum concentrations following single
IM dose
Concentration (ng/ml)
350
300
250
200
150
100
50
0
1
3
4
2
0
Time (hours)
Data on file, Pfizer Inc.
15
LOW POTENTIAL FOR DRUGINTERACTIONS IN VITRO
EVIDENCE
Ziprasidone
in
vitro
study
in
cytochrome
P450
(CYP)
isoforms
l
CYP3A4
substrate

not
CYP2D6,
CYP1A2,
CYP2C9,
CYP2C19
l
No
CYP1A2,
CYP2C9,
CYP2C19
inhibition
l
CYP2D6
and
CYP3A4
inhibition
not
achievable
at
clinically
effective
concentrations
Pharmacokinetic
interactions
via
inhibition
of
CYP
isoforms
not
anticipated
in
the
clinic
e.g.
non-sedating
antihistamines,
S
SRIs,
T
CAs,
b
-blockers,
Ca
channel
blockers
2
Data
on
file,
Pfizer
Inc
16
LOW POTENTIAL FOR DRUGINTERACTIONS IN VIVO
EVIDENCE
Ziprasidone
in
volunteers
l
No
clinically
significant
interaction
with
dextromethorphan
(CYP2D6
substrate)
l
No
clinically
significant
interaction
with
ethinylestradiol
(CYP3A4
substrate)
Confirms
in
vitro
evidence
l
No
clinically
significant
interactions
with
lithium,
cimetidine,
combined
oral
contraceptives
or
Maalox
Data
on
file,
Pfizer
Inc
17
ZIPRASIDONE RECEPTOR PROFILEAND CLINICAL
IMPLICATIONS I
l
V
ery
potent
in
vitro
5HT
and
potent
D
receptor
2A
2
antagonism
l
PET
studies
confirm
5HT
receptor
occupancy
substantially
2
exceeds
D
receptor
occupancy
2
l
High
5HT
/D
ratio
2A
2
efficacy
in
positive
and
negative
symptoms
with
low
EPS
18
ZIPRASIDONE RECEPTOR PROFILE AND CLINICAL
IMPLICATIONS II
l
P
otent
5HT
receptor
agonism,
potent
5HT
receptor
and
1A
1D
very
potent
5HT
receptor
antagonism

moderate
NE
and
2C
5HT
reuptake
inhibition
unique
collection
of
receptor
activities
enhanced
positive
and
negative
symptom
efficacy
efficacy
in
associated
symptoms
of
depression
and
anxiety
a
l
Moderate
receptor
antagonism
1
low
potential
for
postural
hypotension
l
Moderate
H
receptor
antagonism
and
no
antimuscarinic
activity
1
low
potential
for
sedation
and
cognitive
impairment
19
Back-up slides
20
QTc Interval Comparative Data
1FDA Summary Basis of Approval for Risperdal,
Zyprexa and Seroquel 2European Public Assessment
Report 1996 3Litherland et al. Drugs 1997
4Kasper S et al. Eur Arch Psych Clin Neurosc
1999 Zeldox SmPC
21
QTc Interval Comparative Data