The Role of Dopamine

Agonist Extended Release in

Early and Late PD
G. Dewanto
FK Unika Atma Jaya
Jakarta

22/09/2012

G. Dewanto

Therapeutic Principles
Keep the Patient Functioning
Independently as Long as
Possible
Encourage Patients to Remain
Active and Mobile
Individualize Therapy
22/09/2012

G. Dewanto

TREATMENT STRATEGIES OF PARKINSONS

DISEASE
PARKINSONS DISEASE
Idiopathic
Degenerative

Preserving
Independence

Inhibiting Progression

Symptomatic
Neurorestoration
22/09/2012

Progressive

Neuroprotection

G. Dewanto
IMPROVING
QOL

Treatment
Divided into 3 major
categories:
1. Physical (and mental
health)
2. Medications
3. Surgery
22/09/2012

G. Dewanto

Drugs for Symptomatic Treatment of PD

I. Dopaminergic agent
a. Dopamine Precursor : Levodopa
b. Dopa decarboxilase Inhibitor: Carbidopa, Benserazide
c. Dopamine Agonist:
Bromocriptine, Ropinirole, Pramipexole, Apomorfin
d. Presynaptic DA releaser, NMDA-R inhibitor: Amantadine
e. COMT Inhibitor: Entacapone, Tolcapone.
f. MAO-B Inhibitor: Selegiline, Rasagiline
II. Anticholinergic: Trihexyphenidyl, Benztropine

22/09/2012

G. Dewanto

FDA-Approved Medications for

Parkinsons Disease
Anticholinergics
Benztropine (Cogentin), Trihexyphenidyl (Artane)
COMT inhibitors
Entacapone (Comtan), Tolcapone (Tasmar)
Dopamine agonists
Ropinirole (ReQuip), Pramipexole (Mirapex), Bromocriptine
(Parlodel),
Pergolide (Permax), Cabergoline
Levodopa / Carbidopa
Immediate- and sustained-release carbidopa/levodopa
(Sinemet)
, benserazide/levodopa (Madopar)
MAO-B inhibitors
Selegiline (Eldepryl), Rasagaline (Azilect)
NMDA receptor inhibitor
Amantadine (Symmetrel)
22/09/2012

G. Dewanto

L-Dopa is the cornerstone of PD treatment

Levodopa provides antiparkinsonian benefit

over
the entire course of the disease
Levodopa remains the most widely prescribed
antiparkinsonian agent
Nearly all PD patients eventually require
levodopa therapy
22/09/2012

G. Dewanto

Agid et al 1999
Movement
Disorder
Society 2002
7
Rascol et al 2002

Levodopa Therapy has Limitations

Some motor and non-motor PD symptoms may not

respond well
to levodopa

Levodopa treatment long-term complications:

a. Motor complications
b. Non-motor complications

Olanow et al 2001
Agid et al 2002
Movement
Disorder
Society 2002
8

22/09/2012

G. Dewanto

COMPLICATIONS OF LONG-TERM USE

OF LEVODOPA
Motor complications
a. Motor fluctuation
Wearing off, On-off, No-on (akinesia)
b. Dyskinesia (dystonia, chorea, diphasic)
Non Motor complications
a. Sensory symptom
Pain, paresthesia, numbness, akathisia, restless leg syndrome, burning
b. Autonomic symptom
Urinary incontinence, constipation, sexual dysfunction, seborrhea,
sweating, orthostatic hypotension
c. Personality and behavior disturbance
Depression, anxiety, loss of drive, passivity, dependency,,apathy, loss
of motivation, inability to make decision, abulia, confusion,
halucination and psychosis

22/09/2012

G. Dewanto

The Levodopa Therapeutic Window

Narrows with Disease Progression

Plasma levodopa concentrations

Schematic depicting the narrowing of the levodopa therapeutic window

over time

Early
disease

Moderate
disease

Advanced
disease

Efficacy
threshold

Therapeutic
window

22/09/2012

Dyskinesia
threshold

G. Dewanto
Time

10

Obeso et al 2000

In PD, traditional levodopa delivery leads

to pulsatile dopamine levels in the brain
In PD, the ability to regulate
and maintain steady levels of
dopamine in the brain is
reduced due to progressing
neuronal loss

The short half-life

(6090 min) of traditional
levodopa leads to peaks and
profound troughs in plasma
levodopa levels which are
further worsened by
intermittent dosing

Pulsatile plasma levodopa levels leads to pulsatile

levels of dopamine in the brain
22/09/2012

G. Dewanto

11

The first manifestation of pulsatile

levodopa delivery in the brain is
often wearing-off
Symptoms
controlled

Time
Symptom
re-emergence
Traditional levodopa

Pulsatile levels of dopamine in the brain translate into

fluctuations in clinical response
Often the first complaint patients have is that the duration of
symptom control provided by their traditional levodopa becomes
shorter (wears-off) and their symptoms re-emerge before the
next scheduled dose
22/09/2012
12
G. Dewanto

Stacy et al, 2005

The long-term consequence of pulsatile

levodopa delivery in the brain is often
dyskinesia
In PD, pulsatile plasma levodopa levels translates into
pulsatile levels of dopamine in the brain

Pulsatile stimulation of striatal dopamine receptors

Further destabilization of an already unstable basal ganglia

Dyskinesia
22/09/2012

G. Dewanto

13

Dopamine Agonists in the

Treatment of PD
Older approach: adjunct to levodopa
(moderate
to advanced stages of disease)
Newer strategy: start with dopamine
agonist monotherapy and later add
levodopa to reduce
the incidence and severity of motor
complications and obtain a better longterm result
22/09/2012

G. Dewanto

14

What is dopamine agonist?

A drug that directly binds and
activates dopamine receptors
(D1,D2,D3) in the brain and by
so doing mimics the effects of
dopamine
Activation of D2 receptor is
known to be important in
obtaining an anti PD, especially
Pramipexole, Ropinirole and
22/09/2012

G. Dewanto

15

Dopamine Agonist
Bromocriptine
- ergot
- actions: D2 , D3 receptors agonist
- cautions: hypotensive reaction
Lisuride
- ergot
- actions: D1, D2 receptors agonist
- cautions: severe peripheral vascular disease,
coronary disease
22/09/2012

G. Dewanto

16

DA contd
Pergolide
- ergot
- acts: D1, D2, D3 receptors agonist
- cauts: hystory of cardiac disease, confusion
Cabergoline
- ergot
- acts: D2 receptor agonist
- cauts: hypotensive reactions
22/09/2012

G. Dewanto

17

DA contd
Apomorphine
- most powerful DA
- acts: D1, D2 receptors agonist
- injected SC or intranasally
- cauts: emesis

Rotigotine

- non-ergot
- transdermal patch
- FDA approved 2007, voluntary recall 2008

22/09/2012

G. Dewanto

18

DA contd
Pramipexole
- non-ergot
- acts: D2, D3 receptors agonist
- cauts: renal impairment, psychoses
Ropinirole
- non-ergot
- acts: D2, D3 receptors agonist
- cauts: cardiac disease, major psychoses, hepatic
renal imparment
Perachon S, Schwartz JC, Sokoloff P: Functional potencies of a new antiparkinsonian drugs at
recombinant human dopamine D1,D2 and D3 receptors. Eur J Pharmacol 1999;366:293-300

22/09/2012

G. Dewanto

19

Benefits of DA
All DA are less likely to induce
dyskinesias compared to LD (Schrag et
al,1998)

DA can be used as adjuncts to LD

therapy (Lieberman et al,1998; Pinter et al,1999)
Or as monotherapy (Kieburtz et al,1997b; Brooks et
al,1998;Kulisevky et al,1998;Rinne,Bracco et al,1998; Sethi et al,1998)

22/09/2012

G. Dewanto

20

What are the side effect of the

DA?
Nausea, vomiting, postural
hypotension, confusion and
hallucination, constipation, fatique,
vivid dream, peripheral edema with
erythema
Sleep attacks (excessive day time
sleepiness)
(Parkinson Study Group,2000; Rascol et al, 2000, Ferreira et al, 2000;
Hoehn,2000;Schapira, 2000))

uncommonly causes pathologic gambling,

punding and other
impulse control disorder
22/09/2012
G. Dewanto
21

How to use DA?

Start slow, increased gradually over a series

of weeks.
If DA to be withdrawn, then the drugs should
be slowly reduced.
Abrupt cessation of DA may precipitate a
neuroleptic malignant syndrome
(hyperthermia, confusion, rigidity and
autonomic dysequilibrium) ICU
22/09/2012

G. Dewanto

22

Conversion factors for the

DA
Agonist
Pergolide
Pramipexole
Ropinirole
Bromocriptine

Ratio
1
1
5
10

Canesi et al, 1999

22/09/2012

G. Dewanto

23

Treatment of Early Parkinsons

Disease
The Role of DA

22/09/2012

G. Dewanto

24

Cochrane Reviews
Dopamine agonist therapy in early Parkinson's
disease
Stowe R, Ives N, Clarke CE, van Hilten JJ, Ferreira J, Hawker RJ, Shah L,
Wheatley K, Gray R

This meta-analysis confirms that motor

complications are
reduced with dopamine agonists compared to
levodopa
Symptom control is poorer than with levodopa.

22/09/2012

G. Dewanto

25

Database of Abstracts of Reviews of Effects

(DARE)
Dopamine agonists in the treatment of early
Parkinson's disease: a meta-analysis
Baker WL, Silver D, White CM, Kluger J, Aberle J, Patel AA, Coleman CI

Dopamine agonist monotherapy appeared to be

superior to
placebo, but inferior to levodopa.
There were fewer motor complications in
comparison
with levodopa.
22/09/2012

G. Dewanto

26

Treatment of Advanced Parkinsons

Disease
The Role of DA

22/09/2012

G. Dewanto

27

Dopamine Agonists as Adjunct:

Levodopa Sparing Effect
Dopamine agonists as adjunct have a levodopasparing effect
Ropinirole
Ropinirole 3x-daily allows significant reduction in
levodopa dose (31% vs 6% for placebo; p<0.001)1
Requip-PD demonstrated approximately 30%
levodopa dose reduction vs placebo2
Pramipexole
Trial data suggests that a short-term levodopa dose
reduction of between 35 and 50% can be anticipated3,4
Rotigotine
Daily application of the rotigotine patch allows a mean
reduction of 53% in levodopa dose (p=0.018)5
1. Lieberman A et al. Neurology 2001;51:135762; 2. Requip-PD SmPC, 2007; 3. Pinter
MM et al. J. Neural Transm. 2000;107;130723; 4. Poewe WH et al Lancet Neurol
2007;6:51320 5: 23542. 5. Metman et al Clin Neuropharmacol 2001;24:1639

22/09/2012

G. Dewanto

28

Efficacy of DAs is well established

in the treatment of both
early and late PD

DAs in early PD

DAs in late PD

Efficacious as monotherapy

Efficacious as adjuvant therapy to

levodopa

Improve parkinsonism symptoms and

rarely induce dyskinesias or motor
fluctuations

Significantly reduce off time

Reduce long-term incidence of motor

complications

May lessen dyskinesias

22/09/2012

G. Dewanto

29

Beluzzi et al, 2004; Tolosa & Katzenschlager 2007

Current treatment recommendations

Treatment strategy should balance the benefits of early
treatment with risk of long-term motor complications
resulting from treatment1,2

Dopamine agonists are effective in reducing the

symptoms of Parkinsons disease1,2
Dopamine agonists are effective in reducing the later
incidence of motor complications associated with levodopa3

Dopamine agonists may be an appropriate treatment

strategy as monotherapy in early-stage patients, or later
as adjunct to levodopa
1. Miyasaki JM et al. Neurology 2002; 58:117; 2.Olanow CW et al. Neurology 2001;56 (suppl 5):S1S88; 3.
Rascol O et al. Poster presented at the 9th International Congress of Parkinsons Disease and Movement
Disorders, New Orleans, Louisiana, USA, 5 8 March 2005.

22/09/2012

G. Dewanto

30

 Generally, however, pt below the age

of 65, or above the age of 65 with no
other comorbidity are started on a
dopamine agonist as an initial
therapy.

Foltynie T, Lewis S, Barker RA: Parkinsons Disease, Your question

answered, Churchill Livingstone, Edinburg,2003,69

22/09/2012

G. Dewanto

31

DOPAMINE AGONIST

Pramipexole
provides benefit as monotherapy,
and adjunct to carbidopa/levodopa
improves motor functions and ADL
improves tremor

22/09/2012

G. Dewanto

32

 All dopamine agonists share a potent

activity at dopamine D2 receptors, but
they differ with respect to their effects on
other types of CNS receptors, including D1
receptors and their pharmakokinetic
profile.
Differences in the elimination half life are
the main determinants of the duration of
action of orally administered dopamine
agonist, ranging from 1-3 hours for lisuride
to
70-105
hours
for
cabergoline.
22/09/2012

Van Laar T: Parkinsons DiseaseG.Related

Parkinsonism and related
DewantoPharmacotherapy in : Wolters Ech: 33
disorders, VU University Press Amsterdam,2007,p 223

Review of the pharmacokinetic and pharmacodynamic

properties of currently available oral dopamine agonist
Agonist

Receptor profile
D1

Apomorphin
e (s.c.)

Pharmacokinetic
properties

D2

5-HT

Bioavailabi
lity (%)

Tmax (min)

T el. (h)

+++

100

5-15

0.5

Bromocriptin
e

++

70-100

4-8

Cabergoline

+++

60-80

120-240

70-105

+++

Pergolide

+++

20

60-120

30

Pramipexole

+++

>90

60-180

10

Ropinirole

+++

65

80

Lisuride

1-3

0=no binding affinity, + - +++ = mild to strong binding affinity

Van Laar T: Parkinsons Disease-related Pharmacotherapy. Parkinsonism and
Related Disorders. VU University Press. Amsterdam, 2007 : 223.

22/09/2012

G. Dewanto

34

Continuous Drug Delivery

(CDD)
Physiological stimulation of striatal
dopamine receptors is generally
continuous and tonic
Dopaminergic tone is lost in PD
Pulsatile stimulation by short-acting drugs
such as levodopa may contribute to motor
complications
Longer-acting dopamine agonists such as
pramipexole contribute to more
continuous dopaminergic stimulation and
lower the incidence of motor complications
Olanow
36 W, et al. Lancet Neurol 2006;5(8):677-87.
Stocchi F, Parkinsonism Relat Disord 2009;15 Suppl 1:S9-S15.

36

Pramipexole Extended
Release
- Trials in Early Parkinsons
Disease
- Trials in Advanced
Parkinsons Disease
37
37

Pramipexole Extended Release in Early

PD
Design
599 enrolled / 539 entered / 539 treated / 2:2:1
randomization

Pramipexole ER (n = 223)
Pramipexole IR (n = 213)
Placebo (n = 103)

Double-blind, double-dummy, placebo-controlled, randomized, parallel

group trial
Flexible up-titration from 0.375 to 4.5 mg/day over 7 weeks, then
maintenance phase.
Levodopa allowed as a rescue medication, during maintenance phase
Poewe
38 W, et al. Poster, Movement Disorder Society 13th International Congress, Paris, France,
June 7-11, 2009, We-185.

Pramipexole Extended Release in Early

PD
Objectives
At Week 18:
To demonstrate superiority of pramipexole ER
vs. placebo
At Week 33:
To demonstrate non-inferiority of pramipexole
ER vs. pramipexole IR
To demonstrate maintenance of efficacy over
33 weeks
Poewe
39 W, et al. Poster, Movement Disorder Society 13th International Congress, Paris, France,
June 7-11, 2009, We-185.

Pramipexole Extended Release in

Early PD
Main Efficacy Endpoints
Primary

UPDRS II+III score

Key
secondary

% Clinical Global ImpressionImprovement

(CGI-I) and Patient Global Impression
Improvement (PGI) responders

Selected
other
secondary

40

Data on file

% UPDRS II+III responders (20%

improvement)
UPDRS I , II , III scores separately
% of patients requiring levodopa rescue
Quality-of-life scales: Parkinson Disease
Questionnaire39 items (PDQ-39) and EuroQoL
(EQ-5D) (change from baseline)

Pramipexole Extended Release in

Early PD
Safety Endpoints
Incidences of adverse events

Proportions of withdrawals due to adverse events

Vital signs and weight
Epworth Sleepiness Scale (ESS)
Modified Minnesota Impulsive Disorders Interview
(mMIDI): subscales for pathological gambling,
compulsive buying, compulsive sexual behaviour
Safety laboratory tests

41
41

Pramipexole Extended Release in

Early PD
Conclusion Efficacy
18-week analysis:
Superiority of pramipexole ER vs. placebo was
demonstrated at Week 18 for both the primary
endpoint (UPDRS II+III) and the key secondary
endpoints (CGI-I and PGI-I)
33-week analysis:
Non-inferiority of pramipexole ER vs. pramipexole
IR was demonstrated at Week 33
Maintenance of efficacy was shown after 33
weeks of treatment
Poewe
42 W, et al. Movement Disorder Society 13th International Congress, Paris, France, June 7-11,
2009, Poster We-185.

Pramipexole Extended
Release in Early PD
Conclusion Safety
The safety and tolerability of
pramipexole ER was
comparable to pramipexole IR,
at similar mean daily dose and
dose distribution, and
comparable duration of
treatment

Poewe
43 W, et al. Movement Disorder Society 13th International Congress, Paris, France, June 7-11,
2009, Poster We-185.

Pramipexole Extended Release in Early PD

Most Frequent Adverse Events at Week 33
AEs with frequency greater than with placebo and 5% in any pramipexole group

Patients treated

Placebo

Pramipexole ER

Pramipexole IR

N (%)

N (%)

N (%)

103

223

213

Patients with any AE

80 (77.7)

189 (84.8)

172 (80.8)

Somnolence

15 (14.6)

81 (36.3)

70 (32.9)

Nausea

9 (8.7)

48 (21.5)

51 (23.9)

Constipation

2 (1.9)

32 (14.3)

25 (11.7)

Dizziness

7 (6.8)

26 (11.7)

25 (11.7)

Fatigue

4 (3.9)

14 (6.3)

12 (5.6)

Dry mouth

1 (1.0)

12 (5.4)

8 (3.8)

Peripheral oedema

4 (3.9)

12 (5.4)

18 (8.5)

Headache

6 (5.8)

7 (3.1)

15 (7.0)

No relevant difference was observed between the two pramipexole formulations

44

Poewe W, et al. Short communication, 13th Congress of the EFNS, Florence, Italy, September 14, 2009.

44

Pramipexole Extended Release in

Advanced PD
Design
605 enrolled / 518 entered / 517 treated / 1:1:1 randomization

Pramipexole ER (n = 165)
Pramipexole IR (n = 175)
Placebo (n = 178)
Double-blind, double-dummy, placebo-controlled, randomized, parallel group
Flexible up-titration from 0.375 to 4.5 mg/day over 7 weeks (dose to be
increased in all patients who were not at least a little better on the Patient
Global ImpressionImprovement (PGI-I), then maintenance phase.
Concomitant levodopa could be reduced in case of dopaminergic adverse
events
Schapira AHV, et al. Movement Disorder Society 13th International Congress, Paris,
45 France, June 7-11,
2009, Poster We-199.

45

Pramipexole Extended Release in

Advanced PD
Objectives
To demonstrate superiority of pramipexole ER
vs. placebo on UPDRS II+III (primary endpoint)
and off time (key secondary endpoint) at
Week 18 (confirmatory analysis)
To demonstrate maintenance of efficacy at 33
weeks (descriptive analysis)
To compare pramipexole ER and pramipexole
IR efficacy (descriptive comparison, no formal
statistical non-inferiority test)
Schapira
46 AHV, et al. Movement Disorder Society 13th International Congress, Paris, France, June 7-11,
2009, Poster We-199.

Pramipexole Extended Release in

Advanced PD
Safety Endpoints
Incidence of adverse events
Proportion of withdrawals due to adverse events
Vital signs and weight
Epworth Sleepiness Scale (ESS)
Modified Minnesota Impulsive Disorders Interview
(mMIDI): subscales for pathological gambling,
compulsive buying, compulsive sexual behaviour
Safety laboratory tests

47
47

Pramipexole Extended Release in

Advanced PD
Conclusion Efficacy
Superiority of pramipexole ER vs. placebo was
demonstrated at Week 18 for both the primary
endpoint (UPDRS II+III) and the key
secondary endpoint (off time)
Maintenance of efficacy was shown after 33
weeks of treatment
The efficacy of pramipexole ER was
comparable to pramipexole IR, at similar mean
daily dose, dose distribution, and comparable
duration of treatment
Schapira AHV, et al. Movement Disorder Society 13th International Congress, Paris,
48 France, June 7-11,
2009, Poster We-199.

48

Pramipexole Extended Release in

Advanced PD
Conclusion Safety
Pramipexole was well tolerated overall, with a
similar occurrence of adverse events (AEs) at 18
weeks in the pramipexole ER group (54.9%)
compared to placebo (55.6%) and a numerically
lower percentage of AEs compared to
pramipexole IR (64%).

Schapira AHV, et al. Movement Disorder Society 13th International Congress, Paris,
49 France, June 7-11,
2009, Poster We-199.

49

Pramipexole Extended Release in Advanced

PD
Most Frequent Adverse Events at Week 18
Adverse events (AEs) more than with placebo and 5% in any pramipexole group

Patients treated

Placebo

Pramipexole ER

Pramipexole IR

n (%)

n (%)

n (%)

178

164

175

99 (55.6)

90 (54.9)

112 (64.0)

14 (7.9)

27 (16.5)

32 (18.3)

Somnolence

24 (13.5)

18 (11.0)

24 (13.7)

Nausea

18 (10.1)

18 (11.0)

20 (11.4)

Headache

5 (2.8)

11 (6.7)

7 (4.0)

Constipation

9 (5.1)

11 (6.7)

10 (5.7)

Hallucination

1 (0.6)

9 (5.5)

9 (5.1)

Dizziness

9 (5.1)

8 (4.9)

18 (10.3)

Vomiting

5 (2.8)

2 (1.2)

10 ( 5.7)

Patients with any AE

Dyskinesia

The AE profile was similar between ER and IR groups

Less AEs reported in the ER group than in placebo and
IR groups
50

Schapira AHV, et al. Short communication, 13th Congress of the EFNS, Florence, Italy, September 14, 2009. 50

Pramipexole Extended Release in Advanced

PD
Most Frequent Adverse Events at Week 33
Adverse events (AEs) more than with placebo and 5% in any pramipexole group
Placebo
n (%)
Treated

Pramipexole IR
n (%)

140 (100.0)

120 (100.0)

135 (100.0)

9 (6.4)

21 (17.5)

24 (17.8)

Somnolence

21 (15.0)

19 (15.8)

22 (16.3)

Nausea

14 (10.0)

14 (11.7)

14 (10.4)

Headache

5 (3.6)

11 (9.2)

7 (5.2)

Constipation

7 (5.0)

9 (7.5)

8 (5.9)

Dizziness

7 (5.0)

7 (5.8)

18 (13.3)

Insomnia

4 (2.9)

7 (5.8)

8 (5.9)

Fall

8 (5.7)

7 (5.8)

5 (3.7)

Anorexia

3 (2.1)

7 (5.8)

0 (0.0)

Hallucination

2 (1.4)

6 (5.0)

10 (7.4)

Cataract

4 (2.9)

4 (3.3)

7 (5.2)

Arthralgia

4 (2.9)

3 (2.5)

7 (5.2)

Dyskinesia

51

Pramipexole
ER
n (%)

Schapira AHV, et al. Short communication, 13th Congress of the EFNS, Florence, Italy, September 14, 2009.

Pramipexole Extended Release

Switch Trial in Early PD

Double-blind, double-dummy, active-controlled,

randomized, parallel group

Two treatment arms: pramipexole ER and

pramipexole IR (2:1ratio)

Overnight switch from pramipexole IR (open

label) to pramipexole ER or pramipexole IR
(double blind)

Dose adaptation allowed at Week 4 and 5

Final assessment at Week 9

Rascol O, et al. American Academy of Neurology 61st Annual Meeting, Seattle, Washington,
USA, April
52
25-May 2, 2009, Poster P06-152.

52

Pramipexole Extended Release Switch Trial

in Early PD
Objectives

To assess if patients with early PD can be successfully

switched* (overnight) from pramipexole IR to pramipexole
ER

To establish if this successful switch can be obtained with

or without dose adaptation

To provide information about the dose conversion ratio

(mg:mg) from pramipexole IR to pramipexole ER

* Definition of successful switch = No worsening of the

UPDRS II+III score by more than 15% from baseline and no
discontinuation due to a drug-related adverse event
Rascol O, et al. American Academy of Neurology 61st Annual Meeting, Seattle, Washington,
USA, April
53
25-May 2, 2009, Poster P06-152.

Pramipexole Extended Release Switch Trial

in Early PD
Conclusion Efficacy & Tolerability

96% of patients switched to pramipexole extended release

(ER) completed the study

84.5% of patients switched to ER maintained efficacy after

a possible dose adaptation and of these, 82.8% maintained
efficacy at the same pramipexole total daily dose

On all secondary endpoints, efficacy was numerically better

with pramipexole ER compared to pramipexole immediate
release (IR)

Both pramipexole ER and IR were well tolerated

An overnight switch from pramipexole IR to pramipexole ER

can be considered initially at the same total daily dose (1:1
mg ratio)

Rascol
55 O, et al. Movement Disorder Society 13th International Congress, Paris, France, June 7-11, 2009,
Poster Th-255.

Pramipexole Extended
Release
and Parkinsons Disease
Conclusions

Pramipexole Extended Release in

Parkinsons Disease
Conclusions

In summary, pramipexole ER provides

effective treatment for the early and
advanced stages of PD. Pramipexole ER is as
effective and well tolerated as pramipexole IR
Patients can be switched overnight from
pramipexole IR to pramipexole ER, initially at
the same daily dose
In principle, by its extended release
formulation, pramipexole ER provides more
continuous drug delivery than pramipexole IR
57
57

Pramipexole Extended Release in

Parkinsons Disease
General Considerations

Treatment convenience and compliance:

Pramipexole ER given once a day is more convenient
than pramipexole IR t.i.d. and therefore may increase
treatment compliance, which may result in optimised
efficacy and tolerability
Reduction of pill burden and decrease of erratic drug
intake are key success factors in PD treatment

The psychological impact of a once-daily dosing regimen in

de novo PD patients
Newly diagnosed PD patients may experience more ease
in coping with their illness via a simpler, once-daily
dosing regimen

58
58

22/09/2012

G. Dewanto

59

Thank
You
22/09/2012

G. Dewanto

60

 All dopamine agonists share a potent

activity at dopamine D2 receptors, but
they differ with respect to their effects on
other types of CNS receptors, including D1
receptors and their pharmakokinetic
profile.
Differences in the elimination half life are
the main determinants of the duration of
action of orally administered dopamine
agonist, ranging from 1-3 hours for lisuride
to
70-105
hours
for
cabergoline.
22/09/2012

Van Laar T: Parkinsons DiseaseG.Related

Parkinsonism and related
DewantoPharmacotherapy in : Wolters Ech: 61
disorders, VU University Press Amsterdam,2007,p 223

Review of the pharmacokinetic and pharmacodynamic

properties of currently available oral dopamine agonist
Agonist

Receptor profile
D1

Apomorphin
e (s.c.)

Pharmacokinetic
properties

D2

5-HT

Bioavailabi
lity (%)

Tmax (min)

T el. (h)

+++

100

5-15

0.5

Bromocriptin
e

++

70-100

4-8

Cabergoline

+++

60-80

120-240

70-105

+++

Pergolide

+++

20

60-120

30

Pramipexole

+++

>90

60-180

10

Ropinirole

+++

65

80

Lisuride

1-3

0=no binding affinity, + - +++ = mild to strong binding affinity

Van Laar T: Parkinsons Disease-related Pharmacotherapy. Parkinsonism and
Related Disorders. VU University Press. Amsterdam, 2007 : 223.

22/09/2012

G. Dewanto

62