Proposed dose equivalence for rapid switch between dopamine receptor agonists in Parkinson's disease: A review of the literature

Clinical Therapeutics/Volume 28, Number 1, 2006

Proposed Dose Equivalence for Rapid Switch Between Dopamine Receptor Agonists in Parkinson's Disease: A Review of the Literature St6phane Thobois, MD, PhD HOpital Neurologique Pierre Wertheimer, Service de Neurologie C, Lyon, France ABSTRACT Background: Progressive reduction of the dose of

one dopamine receptor agonist and simultaneous, progressive dose escalation of another is a frequently used strategy for controlling motor symptoms of Parkinson's disease (PD) or avoiding specific adverse events. Rapid switch has been proposed as an alternative that might reduce the need for such major limitations as the possible exacerbation of symptoms and the need to monitor patients for several weeks. However, the equivalence of doses of dopamine receptor agonists before and after switching drugs remains empirical because few clinical trials have addressed this issue. Objective: The aim of this review was to use the available data from the literature to calculate conversion factors for rapidly switching between dopamine receptor agonists in patients with PD. Methods: Using the MEDLINE and Cochrane Library Central databases, we selected clinical trials that allowed paired comparisons of bromocriptine with the most frequently prescribed dopamine receptor agonists in PD (ie, pergolide, piribedil, pramipexole, and ropinirole). From these data, we calculated dose equivalents of optimal daily doses for each pair of dopamine receptor agonists. Results: Six studies comparing 2 dopamine agonists and 4 studies analyzing the switch between dopamine agonists were selected. The proposed conversion factors were 1:6 for bromocriptine to piribedil, 1:6 for pergolide to ropinirole, 10:6 for bromocriptine to ropinirole, 10:1 for bromocriptine to pergolide, and 10:1 to 10:1.5 for bromocriptine to pramipexole. Conclusions: The conversion factors proposed in this article, based on a literature analysis, could facilitate rapid switches between dopamine receptor agonists in patients with PD, but they must first be confirmed in prospective, double-blind, randomized clinical trials. (Clin Ther. 2006;28:1-12) Copyright @ 2006 Excerpta Medica, Inc. January2006

Key words: dopamine receptor agonist, Parkinson's disease, bromocriptine, piribedil, pergolide, pramipexole, ropinirole, conversion, dose equivalence, switch.

INTRODUCTION

Levodopa plus dopamine decarboxylase inhibitors (DDIs) have long been used in Parkinson's disease (PD) and remain the most effective and frequent treatment for this indication. 1 Treatment with levodopa plus DDI does, however, have limitations, such as motor fluctuations and dyskinesia; in addition, this combination's potential toxicity remains a subject of debate. 1 Since the early 1980s, dopamine receptor agonists have been available to treat patients with PD who experience a deterioration of response to levodopa plus DDI. Since the introduction of bromocriptine, an ergot derivative, as the first commercially available dopamine receptor agonist, other dopamine receptor agonists have become available for clinical use. Bromocriptine, pergolide, piribedil, pramipexole, and ropinirole are currently the most frequently prescribed dopamine receptor agonists worldwide. Generally, dopamine receptor agonists are combined with levodopa plus DDI, particularly in patients with motor fluctuations. Dopamine receptor agonists have been shown to be efficient for managing the symptoms of early PD when prescribed as monotherapy and for improving motor fluctuations and dyskinesia when prescribed in combination with levodopa plus DDI. 2-18 In addition, postponing the introduction of levodopa Accepted [or pubfication November 14, 2005. ExpressTrackonline publication December15, 2005. doi:l 0.101 6/j.clinthera.2005.1 2.003 0149-2918/06/$19.00 Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2006 Excerpta Medica, Inc.

3

Clinical Therapeutics

plus DDI to patients newly diagnosed with PD can delay the onset of motor complications. 11 Clinicians frequently change a patient's treatment from one dopamine receptor agonist to another to improve control of motor symptoms of PD or to avoid specific adverse events (AEs), such as those induced by the use of ergot-derivative dopamine receptor agonists. 19 Indeed, the response (or lack of response) to one dopamine receptor agonist is not predictive of the response (or lack of response) to another. 2° Usually, clinicians progressively reduce the dose of the original dopamine receptor agonist and simultaneously escalate the dose of the new dopamine receptor agonist. However, this method has a number of limitations. First, it requires patient monitoring for several weeks. Second, there is a risk that PD symptoms may be exacerbated, and even that AEs may occur and hospitalization may be required. 21 As an alternative, it has been proposed to replace these slower, progressive titrations by rapid or overnight switch. This approach has been well tolerated in some studies and could improve compliance. 21,22 However, even when the switch is performed more rapidly, it is still possible that some of the same risks as a gradual switch could be encountered. The conversion factors (ie, dose equivalence) of dopamine receptor agonists have been generally established via empirical clinical experience, but they often remain specific to each study. 7'8'12'14-17'20-28 Few published trials that have addressed the switch between dopamine receptor agonists have been designed to address the issue of dose equivalence before and after changing drugs. 21,22,25,28 These trials are summarized in the present article. To calculate conversion factors for rapidly switching between dopamine receptor agonists, we performed a literature review and selected clinical studies that aimed to compare their efficacy and safety in patients with PD. These studies allowed separate comparisons of pergolide, piribedil, pramipexole, and ropinirole with bromocriptine. Using these data, conversion factors for these compounds were calculated. M ETH O DS

A literature search was conducted, using MEDLINE and the Cochrane Library Central Database, covering a 30-year period (1975-2005). The search terms used were: Parkinson's disease, treatment, dopamine

agonists, switch, bromocriptine, pergolide, ph'ibedil, 2

pramipexole, and ropinh'ole. Clinical trials of dopamine receptor agonists for the treatment of PD were selected. These results were further screened and selected if they met any of the following criteria: (1) report of paired comparison of dopamine receptor agonists or switch between 2 dopamine receptor agonists; (2) use of bromocriptine as the basis of comparison with another dopamine receptor agonist; (3) precise report of drug dosages; (4) use of established scales to assess patients' disability; (5) French marketing authorization and indication for use in patients with PD for the dopamine receptor agonists under study (ie, bromocriptine, pergolide, piribedil, pramipexole, and ropinirole); and (6) English-language report. From these data, we calculated dose equivalents of optimal daily doses for each pair of dopamine receptor agonists. The conversion factors were derived from those used in the studies comparing one dopamine agonist with bromocriptine. For dopamine agonists that had not been compared directly one against the other, the conversion factor was calculated as follows: conversion factor for dopamine agonist A to bromocriptine, Z:Y; conversion factor for dopamine agonist B to bromocriptine, X:W. The conversion factor for dopamine agonist A to B was then determined. RES U LTS All clinical trials that fulfilled the criteria described in "Methods" are summarized in the table. Comparison of Piribedil and Bromocriptine Trial Results The double-blind Parkinson-CONTROL study compared the long-term efficacy of fixed doses of piribedil (a non-ergot-derived dopamine-2/dopamine-3 receptor agonist) and bromocriptine in patients with PD whose symptoms were insufficiently controlled by levodopa (<600 mg/d) plus DDI. 23 Most patients (55.5%) were male, and the mean (SD) age was 65.2 (7.7) years. Participants were randomly allocated to 2 groups, and treatment was increased to 150 mg/d in the piribedil group (n = 210) and 25 mg/d in the bromocriptine group (n = 215). The starting dose was 50 mg/d for the piribedil group and 1.25 mg/d for the bromocriptine group. The dose was increased every 2 weeks by steps of 50 mg in the piribedil group up to 150 mg/d. In the bromocriptine group, the increments were not defined, but the maximum dose was 25 mg/d. Volume 28 Number 1

S. T h o b o i s

~ ~ ,--:. v

~-

•- ~

~

~h

-

8 > o o ~-

E

o~

~

E

._~ m

o -~ ~ "-

Z

~ r~

0

I'-,,

'm

°

•

n

o~

~

0

-."q,

.~v~

~

~

~

'-'

E~"

,-,-u ~ ' -

z

~

r-

.-~

.~_

~"

"~

0

c~

~"

~

E

,~ r<

~.

o

U

O_

~

o ~ O

~,

.~

~

n

w

.~

c'-

~

o~

~

~

~

~

~

._G

~

Q

..-G

~

> c~ E oo

~

E q,

"G~ . _

,.._..,

~_ o. r~

0

c'-

t-

cO c~ 'm

0 ×

b,O

o4

"B_

~

,~ ~

,~

o

~ b~ ,-

v - ~

~

",~

O

~®~= nb~ ~ ®~_

._

~ ~ - ~ ._

~-

0

O

v

q~

~

._

t-

Q._ 0

~..

t-

,0

~ ..G .,~

O._

,--

E

~

O_

U

¢h

O

U

n

o

.~

~.~

•

~- -

w

~

o ~

°

..0 0

"B_

.

"-6

n

._

O

o .--

L9

Q

~.-

O_

-2

~

~

~

=~

.2_

_

'm

~

.

~ ' ~ _ ~ - ~ •-

"~

o v

~,~

.-

E

0

=~-

o!. ® o !

~ -'~~ . ,=: ~~

o

~

...2_ .~ ~

~-

~

~

~

= n

u

ouq

.v-

o E

® ~

~

~ ~=. ~

® .. ~ E ~£

~-u

c~

"~~

i-

= ~ L

.--

E ~

~

o

U 0

v

v

('-,I

-~

r.4-~_

c'-

.~

= ® o~

..~ ..~

u

o

.~- o .~-

o ~I,~ ,, ~ " °

O_

E.~

~ ~ 0 ~

"~°E o

C,~

.~

~

,_ ~

~ - 6 . 2b,0 °''~ =~

,, . . . .

= ® o ~ o G_Z._G

~

0q.

.~ t- ~ C'No v

,~.

G_~

~

E

o ..0

q~ k. "~

r-

~.2 " - =

0

o

o

~~ ~ c

ct~ O_

E 0 U

0.0 "g,

"&~-

~ o ~

Q

.• -.[--

#~"~ °

.~

~--~ •~_=

~ ~ .~ ~ ~

Z~

-~

~o~

2~

~ b~ ~-0 ~° ~~ t " ~ --

~"

0

g~-~

~ o

Q..

~-

"r-

0

~ E

-

O_

,<-._x -2 t~

b

._

U

cd

U

~~ .--

..0

¢

January2006

bq

-6 tq~ 12_

3

Clinical T h e r a p e u t i c s

~ ~_.~

® --

~

o

~ o

.~ 8 8 ~ . o ~ ~ -~ ® " ~_ o0 ~ O 0 • r8~ -u bO- u ~ 0 ~ ~~ ~ vq ~,- ~~ 0 ~~ , ~ ~ E ~ ® ~ ~..._...,.-2_~ o. 0 ~ ~ ~ ,~ __ r-" " ~ "-¢) r-" ~ -8.--E

v

E ~

,~

,.----~

c-

L/')

"

~

t_u

"-,

,'-" ' - ' " ~ "

w

~r - - ~

,~..o ~ O

"-

o

~~-

~-

0

r7

t-

"-'

•o --

O

"

.--

~- ®.-~ ~ ~ ~ ® ~~ ~ ~ ~ ~ ~ ~= ®~ ~ ~..~.= ~ o~ o 5 ,~ .__. ~ . , u Eo.~ o

o

°

o

×-~.,--,

~, ~ - ~

,~

.,-,

_b,O 0

--~ "G" ® = ..v - ' . = . -

~

,~ 8 - = ~ o

~-

~-

:_E, ~ I~-~

~

.'-' ~ ,

~

m

c~

~

CN

-~

0

"~.

~n ~ _ ~ - I -

I

u"~ ~

~

"~

~8 o ~

o~,,

~

o

.~~. -.~.". .

z

,.,I~

~

' ~ o -~

~oo

~

~

~

~-

'd

• ,.I

~,~-~

a.,,~. °

~'~-'~

~-

.~_

o v

~

~ o~ 5 "=~- ~ ' -

>-u.= ~

0

~_

~ " ~~

,

o ~

~ ,~

~ ~ ~

"~._ .'-'

m

~

.--

.--

v

d o -,

~b~

- ~z_~

o '~

~

i

0 ",~

~'~ 0

-'

=~_,~v.-o

•~_ =.,~

-~

4 o

~ o~

~ o '~ ~ o ~

E ~

E ~ ~

~v~E

~-.o

,~ ~

o..~

"-...~.-

"~

•

•- ~ ~ E ~ ' .~ - ~

CN-~

~,.,,~ -~E

ny~>8 ~_ ~_ ~o ._G

~_~

I~

m

U

.--

c-

.

~

~_.--

~

~

oO

0-~

G_

~oc.,~-~ ~ E

o~-,

~

• ",~ Cxl

0

~-~

P~ Lr~ •

w

'~ E .~ 0 0 0 _ ~ ~.o -o ® . _ . . ~ ~

=° ~ ,_° =.~ 0 E o,~~ ~- .-

c~ .~

....

._.~-~ °~ "~ 0 -0. . . .

"-~ ""

_~,,,

o~

E E '.- o " - " P-.~

._:~.~.__ c-

=

r'./ oo .._~_

.-.,,

--

~ ®c~

.

.--

~

~

~

~

E

E

•-o -o .~ ~ ~'&-" "~-

oO

o~ o~

-~

~

°dF-.. E ~ d d , . ; 4 q~

-¢ "u ,----.~

¢~ ._.~_.~ ,-.

"~

oo

-o~ o

E',.- ~ r-,

~

•-u - u

".~

•~

O

~ ~-

.~

E ~ s _ . ~ - .='- 0 E'~

-o ",~ ~ ~-'c

~ ~_~

E

..

.~-

~ 0

~ "~

r-,

cO

__

x ~-:- ~ E_~-°

<-o ,~ ~ ~ - ~

~_ ~-

0 ~-

.o

_G c~'~_

KE.

c r-,

o ~-

0 8 ~

cc~

f. m

fO

c~

U

v

GJ c- oo GJ GJ O bq

4

O r~

E-~

L9

Volume

28 Number

1

S. T h o b o i s

bq

~4-0

~ 0

n05

~n , '~

.J n

rA . ~q~ .,-z_

< ~

~

~ o

c

,~o ~ o.r_ ~ -5

:5

~ o.

v "<-~.

bO

&

~

~

u

"

~_

rh

~

>--

0 " ~ ~

~ ~

rd

.__~

o -~'° • Z"~

d ~'i

E'A'E 2 o 'u . _ ~

"'~

0

,-,

- - u = -5x . -~~ . - ~ Z "-8 ~ ~. E _ ~ o . 6 ,---~

o< o~

.m

v

,,, .,-z_< ~. ~ ~_.,~ v

o

Z~

>..

-

=

~

h ~ ~.~.~_ E

"_u o A t . "

o

~'m

"'~

o

,- ~ . =

• ~.._.

o~,o ~_S~

_o > ' ~ o

E ~ %~ "- ,~4 . E :5~ ..-...u

r'-, 0

~,

u ~

<

'-

E o

a_ ~.

E o 0

~ E ~~ ~.o ~ ~

,~..

b'~

~

~

h5 ~

,,.~ ,,-G

~

P'--

--

8 " q . ~>---,.._.., u ~,_

=:___ ,o~oTM ~

"~

~n ~7 f n ~ >.~

~-~_~

E~o

q~ m

v

~n ..~ 04

0

,-~

q~

vP'o")

~

o-,

~fi ~- ~ ~ ~>~ '~

---~

,.o

o

--u"

&

_~

E o

O

~

0

II

Z~ "6 O

E ,-

"~

0

~

.,~-~ 0

q~

'u ~

:E~ ~_m II t-

v

I'-,,

°4

-~

",~0o ~- ..~-~ "F~ " . ~ _ ~ o ~,~o~ ~-_~ ~ - ' ~ - ~ ' , u ~ ~'o ,-.-.- o ,-.-.o ~- ~ - o

-- ----~

E

f - - ~ Lf3

""

E v ~_ ~ E ~ ~,~ ~ - ~ E ~ ~-E

II

o

£

o

~n

C).-~

~o~_ v

~o~

~'.c o ~ ' 6

"-

E

E

~"

° =

~

O

q~

O

~ rg

E

=..5;; C)..,_ ..-~,_;; & ~

,~

P2~'~" _~

~ = , ~ o~

~ o

8

E b.6

~o

E

0

r~

~n

0

0

-~

o

E

m

>

o4

= - ~•

o ~ 2 = ~ s rd

"~

0

0

s_s

"~

.£o

"- ~ ~ ' ~ .--

.E

X

~o Z~_

rh

, r-

,~

-m

¢

>..

--u

~ uq

~_ ,- I--

E~z

6£ o U

Januaw2006

E

.m

5

Clinical Therapeutics

i

0

c-

-

"-

z

i

II

n ~ ._"-

~ ~ >,, ~

0 ~

~.-.

~

~ > ...-

bO~ ~ . -® =

~ ~

'm t'h

q.;

..,,

.~ ~ ' -

r',/ ~u C-,l

q~

,-

~._,-

,.-

E

O LJ-

O ~

~

<

.--

~o,.o

I-

~-

~

,~

~

~- o ~ cO

c

o c~

r~

O

>-

"~

,,

Z

0

..0

~.

o_

~ ao

~• --

~ ~ o~ ,~ ' C:)- ~ "7 . _

r0

. ~ ~.~.~ ~

"-

o.~,

~

~.-. q.,., ~ , ~ ~._.~

c

~

~-

0

"~ "~

O ~

..-0

~'E E~'B.- ~

~

=

--~-~ ".C

~-

,~-

c

o

_

'-

".c

~.-

-~~ ~.~ E 0

~ "0

C3 ~ 0

.c

m-~ -~

--

n

~

~

~

.:

m

o2

,, ~

o

~

~c~ 0

E

~

._ C3-~

.~ ~-~,~ ~

o

~

c 0

~q

~

o_d

p~.E_~

~ v-._~ ~ ul

C3 ~

o~ > o~

._J

~5C3 r0

=

.--

n

~

~

._,,,

II u~

u~

E

~8

E

C 3 ~ V ~ m 0

m ".~

13-

~

c r0

O

b

0

_c II

._~

O

6

Volume

28 Number

1

S. Thobois Treatment groups were homogeneous at inclusion: the mean (SD) Hoehn and Yahr stages at baseline were 2.02 (0.5) in the piribedil group and 2.01 (0.5) in the bromocriptine group, and the mean (SD) Unified Parkinson's Disease Rating Scale (UPDRS) III motor scores were 23.8 (9.4) and 24.1 (10.6), respectively. After 12 months of treatment, UPDRS III motor scores were not significantly reduced in either group (mean [SD] changes, -8.7 [9.1] and -8.6 [9.1] in the piribedil and bromocriptine groups, respectively; P = NS). 23 No significant difference was observed between treatment groups. Overall, 60.8% of the piribedil group and 58.1% of the bromocriptine group experienced a response (defined as a >30% decrease in UPDRS III from baseline); the difference between groups was not significant. The activities of daily living (ADL) scores were improved to a similar extent in both groups (mean [SD] changes, -2.6 [5.2] and -2.7 [3.9] in the piribedil and bromocriptine groups, respectively). The mean (SD) levodopa plus DDI dose was 395 (127) mg/d in the piribedil group and 391 (122) mg/d in the bromocriptine group. The frequency and severity of AEs were not significantly different between treatment groups, with digestive disorders being the most commonly experienced AEs. The rates of withdrawals of patients due to AEs were also similar between treatment groups. This study was extended for another year of treatment in a subgroup of 52 patients (n = 27 in the piribedil group and n = 25 in the bromocriptine group). 24 The selection criteria of these patients in this study were not reported. The improvements in PD symptoms that had been noted after 1 year were maintained at the end of the second year. Indeed, the improvement in UPDRS III scores was maintained versus baseline over 24 months in both treatment groups (mean [SD] changes from baseline, -7.5 [10.0] and -7.9 [9.9] in the piribedil and bromocriptine groups, respectively; P = NS between groups). Moreover, the mean (SD) daily dose of levodopa plus DDI was significantly lower in the piribedil group: 376 (123) and 372 (138) mg/d in the piribedil and bromocriptine groups, respectively, at baseline; 355 (125) and 391 (157) mg/d, respectively, at 12 months; and 382 (164) and 434 (151) mg/d, respectively, at 24 months. At the end of the second year, the mean (SD) adjustment to the daily dose of levodopa plus DDI was significantly lower in the piribedil group than the

January2006

bromocriptine group (6 [116] vs 62 [76] mg; P < 0.049). Thus, fixed doses of 150 mg/d of piribedil and 25 mg/d of bromocriptine led to similar clinical improvements and tolerability in patients with PD.

Dose Equivalence Calculation Although the Parkinson-CONTROL study was not designed as an equivalence study, a post hoc analysis was conducted to assess dose equivalence. The analysis suggested noninferiority of piribedil compared with bromocriptine. The ratio was 1:6 for bromocriptine/ piribedil equivalence.

Comparison and Switch of Pergolide and Bromocriptine Trial Results Pezzoli et al 2s performed a single-blind, crossover study with two 12-week periods to compare bromocriptine and pergolide in 68 patients, 57 of whom completed the study, with PD who experienced a declining response to levodopa-plus-DDI monotherapy (36 [63.2%] men and 21 [36.8%] women; mean age, 61.0 years). Mean duration of PD was 6.6 years; mean Hoehn and Yahr stage was 3.15 (range, 2-4). During the first 12-week period, the patients received pergolide or bromocriptine. The dosage was progressively increased to a maximum of 5 mg/d for pergolide and 50 mg/d for bromocriptine. The mean (SD) daily dose was 2.3 (0.8) mg/d for pergolide and 24.2 (8.4) mg/d for bromocriptine. The mean (SD) levodopa plus DDI daily dose was 635.1 (20) and 637.7 (19) mg/d in the pergolide and bromocriptine groups, respectively. For the second 12-week period, the crossover from the one study drug to the other was achieved rapidly using the conversion ratio 1:10 for pergolide to bromocriptine. The New York University Parkinson's Disease Scale (NYUPDS) was used to evaluate the efficacy of each drug after two 12-week periods. 2s Part A (possible range of scores, 0-100) of NYUPDS evaluates ADL; part B (possible range of scores, 0-356) quantifies physical examination; and part C (possible range of scores, 0-84) assesses dyskinesia, dystonia, and psychosis. Higher scores indicate worse symptoms. There were statistically significant benefits for both bromocriptine and pergolide compared with baseline. Indeed, mean (SD) baseline total score was 201.4 (8.1) and decreased to 139.7 (7.4) after pergolide treatment and to 162.7 (7.5) after bromocriptine treatment

7

Clinical Therapeutics (both, P < 0.001 vs baseline). In addition, there was a significant difference between pergolide and bromocriptine (P = 0.01). Pergolide was associated with significantly greater improvements than bromocriptine in ADL scores (between agonists, P = 0.020) and motor scores (between agonists, P = 0.038). These resuits were confirmed by the Clinical Global Impression scales I and II, which indicated that the severity of the disease was significantly improved for 49.1% of patients in the pergolide group and 33.3% of patients in the bromocriptine group compared with baseline (P = 0.011). Accordingly, improvement was observed for 80.7% of patients in the pergolide group and 63.2% of patients in the bromocriptine group (P = 0.004). The results of this study suggest that both pergolide and bromocriptine are effective as adjunctive therapy to levodopa plus DDI. No significant differences were observed for occurrence of dyskinesia, dystonia, or psychosis. 2s Overall, AEs were more frequent in the bromocriptine group; the most common AE was nausea.

Dose Equivalence Calculation The optimal mean dosages of bromocriptine and pergolide were 24.2 (8.4) mg/d and 2.3 (0.8) mg/d, respectively. An approximate 10:1 ratio between the 2 dosages was observed for >50% of patients in the trial. 2s

Comparisons of Ropinirole and Bromocriptine Trial Results The study of Korczyn et a126,27compared the longterm efficacy and tolerability of ropinirole and bromocriptine in patients with early PD and with limited or no previous treatment with a dopamine receptor agonist or levodopa plus DDI. The trial was double blind with 2 parallel groups: 168 patients in the ropinirole group and 167 patients in the bromocriptine group. The mean age of patients was 63 years, and 61% were men. Patients had a Hoehn and Yahr stage 1 to 3 at baseline, and the duration of disease was -25 years. Bromocriptine and ropinirole were titrated upward at weekly intervals. Approximately two thirds of patients (115/168 in the ropinirole group and 110/167 in the bromocriptine group) completed the 3-year follow-up. The initial daily dose was 0.75 mg for the ropinirole group and 1.25 mg for the bromocriptine group. The dose was titrated upward at weekly intervals according to patient's response and

8

tolerance. The titration was performed using 13 dose levels for each drug. The maximum allowed daily dose was 24 mg for ropinirole and 40 mg for bromocriptine. The patients continued to receive the same levodopa dose throughout the stud> Mean (SD) dosages of dopamine receptor agonists at completion were 12.0 (5.6) mg/d for ropinirole and 24.1 (8.2) mg/d for bromocriptine. In both groups, there was an improvement in UPDRS III motor score and UPDRS II ADL over the first 12 weeks, and this improvement was maintained during the study. Among the patients who completed the 3-year follow-up, the motor improvement was 31% in the ropinirole group and 22% in the bromocriptine group (P = NS); the improvement in ADL scores was significantly higher with ropinirole than with bromocriptine (difference, 1.46 points; P = 0.009). These findings suggest that both ropinirole and bromocriptine were effective as monotherapy. More cases of nausea were reported in the ropinirole group than the bromocriptine group (40.5% vs 25.1%, respectively). Other frequent AEs were dizziness (22.6% vs 19.8%) and vomiting (14.9% vs 7.2%). Psychiatric AEs were reported by 16.1% and 13.8% of patients of ropinirole and bromocriptine groups, respectively; the most common events were hallucinations (9.5% vs 9.0%) and confusion (7.7% vs 5.4%). No P values were provided in the original article.

Dose Equivalence Calculation The purpose of the study of Korczyn et a126,27 was not to perform a switch between dopamine receptor agonists. Nevertheless, post hoc analysis was conducted to assess dose equivalence. The ratio of optimal daily dosages for bromocriptine/ropinirole was calculated as 10:5.

Comparison of Pramipexole and Bromocriptine Trial Results Guttman 16 conducted a randomized, double-blind, 3-arm study of placebo versus pramipexole versus bromocriptine in 247 patients with PD who had a declining response to levodopa plus DDI. The study was designed to assess the tolerance and efficacy of pramipexole versus placebo in advanced PD. A bromocriptine group was included to enable comparison between bromocriptine and placebo, but the study was not specifically designed for direct comparison between the 2 dopamine agonists. The duration of the

Volume 28 Number 1

S. Thobois study was up to 9 months. The baseline UPDRS motor scores were 13 in the pramipexole group and 10.25 in the bromocriptine group. The initial dose of pramipexole was 0.37 mg/d. The initial dose of bromocriptine was 1.25 mg/d. The titration was performed every 2 weeks up to a maximum of 12 weeks. The maximum dosages were 30 mg/d for bromocriptine and 4.5 mg/d for pramipexole. Overall, 63.2% of patients were male, the mean duration of disease was 6.6 years, and all patients had a Hoehn and Yahr stage 2 to 4 at baseline. The reduction in UPDRS III motor score was significantly greater with dopamine receptor agonists than with placebo (changes: 34.0% with pramipexole [P < 0.001], 23.8% with bromocriptine [P = 0.01], and 5.7% with placebo)) 6 UPDRS II ADL score improved by 26.7% with pramipexole (P < 0.001), 14% with bromocriptine (P = 0.02), and 4.8% with placebo. No differences in efficacy or AEs were noted between pramipexole and bromocriptine. However, this study was not designed for direct comparison between the 2 drugs.

Dose Equivalence Calculation Although the study was not designed for direct comparison, a post hoc analysis was conducted to assess dose equivalence. The conversion factor for bromocriptine and pramipexole was 10:1 to 10:1.5.

Rapid Switch from Pergolide or Bromocriptine to Ropinirole or Pramipexole Trial Results Goetz et a121 investigated the switch from bromocriptine or pergolide to pramipexole. The conversion factors were 1:10 for pramipexole and bromocriptine and 1:1 for pramipexole and pergolide. The primary end point was the time needed to reach a better UPDRS III score than baseline without incidence of AE. The secondary objective of this study was to compare a rapid (ie, overnight) versus a slow (ie, up to 8 weeks) switch. Sixteen patients with motor fluctuations on a stable dose of levodopa plus DDI (and declining treatment response) were randomized to the slow or rapid group (each, n = 8 ) . 21 At baseline, the mean (SD) daily dose of pergolide equivalent was 2.3 (0.8) mg/d for the rapid titration group and 2.2 (0.5) mg/d for the slow titration group. In each group, one half of the patients switched from bromocriptine and one half from perJanuary2006

golide to pramipexole. In the slow titration group the pramipexole dose was increased weekly to reach the equivalent dosage. No details were provided concerning the increments in which the doses were increased. The patients were followed every week during 8 weeks in both groups. The investigators were blinded to type of switch. The 2 groups were similar in disease stage and severity (baseline mean [SD] UPDRS III motor scores 29.6 [11] in the rapid group and 28.6 [10] in the slow group; P = NS). The mean age of participants was 67 years, and the overall duration of disease was -14 years. The improvement in baseline UPDRS III motor score and the final dose of pramipexole were similar in both groups (score change, -3.6 in the rapid group vs -3.4 in the slow group; both, P < 0.01 vs baseline). 21 The mean pramipexole daily dose in both groups at the end of the study was 2.16 mg in the rapid group versus 2.2 mg in the slow group (P = NS). However, the mean time to reach the primary end point was longer in the slow titration group (2.1 vs 5.3 weeks; P < 0.001) and an increase in parkinsonian signs was observed in 7 patients in the slow titration group (P < 0.001). In addition, serious AEs (hip fractures related to falls) were encountered in 2 patients in the slow titration group. In contrast, no difference was noted in terms of dyskinesia. Four patients experienced an increase of dyskinesias in the rapid titration group and 6 in the slow titration group (P = NS). The aim of an open-label, short-term (4-week) study of Canesi et a122 was to investigate the rapid switch to ropinirole therapy in patients (26 women and 42 men) not satisfactorily controlled by pergolide (n = 46) or bromocriptine (n = 22), alone or in combination with other drugs. The mean (SD) age of the patients was 63.4 (2.4) years. The mean duration of PD was 11.0 (1.1) years, and patients were categorized as Hoehn and Yahr stage 1 to 3. Patients were evaluated at baseline and 4 weeks after the change of dopamine receptor agonist. AEs were not reported. Dose equivalence ratios were selected to maintain relatively stable motor symptoms before and immediately after the switch. 22 The ratio was determined according to preliminary clinical experience and the advice of the manufacturers. A 10:6 bromocriptine/ ropinirole dose ratio and a 1:3 pergolide/ropinirole dose ratio were initially used. However, the 1:3 pergolide/ ropinirole dose ratio was replaced by 1:6 after the withdrawal of patients due to lack of efficacy. Indeed,

9

Clinical Therapeutics with the 1:3 conversion factor, patients receiving ropinirole experienced a worsening of motor symptoms, leading to a further increase in ropinirole dose up to a new conversion factor of 1:6. The mean (SD) ADL scores significantly improved in patients who switched from bromocriptine to ropinirole (from 6.0 [1.1] before the switch and with bromocriptine to 3.3 [2.8] 4 weeks after the switch and with ropinirole; P < 0.05). The ratio used for bromocriptine/ropinirole equivalence was 10:6. However, none of the other UPDRS scores were significantly changed after either type of switch. Four weeks after the switch, the mean (SD) ropinirole dosage was 15.2 (5.5) mg/d in patients previously treated with pergolide (mean [SD] dosage before switch, 2.7 [0.7] mg/d) and 13.2 (5.4) mg/d in patients previously treated with bromocriptine (mean [SD] dosage before switch, 18.5 [4.1] mg/d). These results suggest that the dose equivalence ratios of 1:6 for pergolide/ropinirole and 10:6 for bromocriptine/ropinirole were useful for switching to ropinirole. A study by Gimenez-Roldan et al 2s compared 3 dose equivalence ratios (5:1, 3:1, and 2:1) for a switch from bromocriptine to ropinirole. It was concluded that the optimal ratio for bromocriptine/ropinirole was -2:1. This study included 23 patients (9 males, 14 females; mean [SD] age, 69.9 [5.2] years) with advanced PD not well controlled by bromocriptine plus levodopa plus DDI. The mean (SD) bromocriptine dose at baseline was 18.9 (6.5) mg/d. The switch from bromocriptine to ropinirole was based on 3 different ratios (5:1, 3:1, and 2:1) with a slow titration. During the first month, bromocriptine was progressively reduced to discontinuation. In parallel, ropinirole was gradually increased at a rate of 0.75 mg per week and then adjusted to the ratio of 5:1. If the response was unsatisfactory, a further increase was performed to a 3:1 ratio. If the response was still not sufficient, then the ropinirole dose was further increased to reach the 2:1 ratio. The mean (SD) levodopa plus DDI dose at baseline was 715 (231) mg/d. The trial lasted 3 months, and 19 patients completed the stud> The end point mean (SD) dosages of ropinirole were 10.1 (2.5) mg/d in the 2:1 ratio group, 4 (1.4) mg/d in the 3:1 ratio group, and 3.6 (2) mg/d in the 5:1 ratio group. The mean (SD) UPDRS ontreatment motor score did not differ significantly between bromocriptine and ropinirole using the 5:1

10

(20.2 [11.4] vs 19.1 [11.1]; P = NS) and 3:1 ratios (20.2 [11.4] vs 18.3 [9.8]; P = NS). The 2:1 ratio was the only one found to provide a significant improvement of the UPDRS on-treatment motor score (mean [SD] UPDRS, 15 [9] with ropinirole vs 20.2 [11.4] with bromocriptine; P = 0.03). With the other ratios, the UPDRS motor score did not change in 44% of patients, worsened in 37% of patients, and improved in 19% of patients. Dyskinesias increased by 53.8% with the 2:1 ratio (P = NS). With the 5:1 ratio, 1 patient experienced painful off-treatmentperiod dystonia. The occurrence of AEs was not related to the ratio used.

Conversion Factors for Switching Between Dopamine Receptor Agonists The clinical trials (summarized in the table) described in this article were used to define the following conversion factors between dosages of dopamine receptor agonists: 1:6 for bromocriptine to piribedil, 23,24 1:6 for pergolide to ropinirole, 10:6 for bromocriptine to ropinirole, 22,26,27 10:1 for bromocriptine to pergolide, 25 and 10:1 to 1.5 for bromocriptine to pramipexole. 16,21 Although no clinical trials have been performed on direct comparisons, the ratios of ropinirole/ piribedil and pergolide/piribedil may be calculated by extrapolation using the values of the other conversion factors. These proposed conversion factors for optimal daily doses are summarized in the figure. DISCUSSION

A direct comparison between slow and rapid titration for dopamine receptor agonist change has only, to our knowledge, been performed in the study by Goetz et al. 21 This issue is interesting for a number of reasons: (1) an overnight switch can be done quickly and avoid a prolonged mixed intake of dopamine receptor agonists, which might improve patient compliance; (2) this strategy could be less costly; (3) it would be simpler for both the patient and the clinician; and (4) a more rapid switch could potentially reduce the risks for AEs related to the temporary prescription of 2 dopamine receptor agonists. Goetz et a121 found a benefit in the rapid switch group. Indeed, the time to reach a UPDRS III motor score better than that recorded at baseline was significantly shorter in the rapid titration group, whereas worsening of parkinsonian syndrome and serious AEs were only reported in the slow titration group. Thus, in the small study by Goetz et al, 21 a rapid switch

Volume 28 Number 1

S. Thobois

xlO , ~ ~

Piribedil ~ ~ x x 6 0

2.

3. Bromocriptine

Ropinirole ~ X O . 6

X0 . 1 ~

Pergolide/pramipexole

x6 Figure. Proposed conversion factors for determining the optimal daily doses for rapidly switching between dopamine receptor antagonists in patients with Parkinson's disease, based

4.

5.

6.

on data from the literature. 16,21-26,28 For bromocriptine to pramipexole, the exact ratio is 10:1 to 10:1.5, depending on the study. 7.

was well tolerated. This further suggests that a rapid switch may reduce the risk for AEs, although that hypothesis remains to be confirmed in large, double-blind, randomized trials. Moreover, the findings of Goetz et a121 are limited by the small size of the study sample. It should also be noted that the proposed 10:5 ratio for bromocriptine/ropinirole switch, based on the work of Korczyn et al, 26,27 is close to the 10:6 ratio obtained directly in the study by Canesi et al. 22 However, the study by Canesi et a122 also had limitations, most notably the short treatment duration, the limited sample size, and the lack of AE reporting.

8.

9.

10.

11.

CONCLUSIONS

This literature analysis is a first attempt to define conversion factors that might facilitate rapidly switching between dopamine receptor agonists in patients with PD. We calculated ratios of 1:6 for bromocriptine to piribedil, 1:6 for pergolide to ropinirole, 10:6 for bromocriptine to ropinirole, 10:1 for bromocriptine to pergolide, and 10:1 to 10:1.5 for bromocriptine to pramipexole. However, these proposals require confirmation in prospective, double-blind, randomized clinical trials.

12.

13.

REFERENCES

1. Olanow cw, Agid Y, Mizuno Y, et al. Levodopa in the treatment of Parkinson's disease: Current controversies January2006

14.

[published correction appears in Mov Disord. 2005;20: 645]. Mov Disord. 2004;19:997-1005. Thobois S, Delamarre-Damier F, Derkinderen P. Treatment of motor dysfunction in Parkinson's disease: An overview. Clin Neurol Neurosurg. 2005;107:269-281. Rinne UK. Early combination ofbromocriptine and levodopa in the treatment of Parkinson's disease: A 5-year follow-up. Neurology. 1987;37:826-828. Montastruc JL, Rascol O, Senard JM, Rascol A. A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkinson's disease: A 5-year follow-up. J Neurol Neurosurg Psychiatry. 1994;57: 1034-1038. Adler CH, Sethi KD, Hauser RA, et al, For the Ropinirole Study Group. Ropinirole For the treatment of early Parkinson's disease [published correction appears in Neurology. 1997;49:1484]. Neurology. 1997;49:393-399. Hely MA, Morris JG, Traficante R, et al. The Sydney Multicentre Study of Parkinson's disease: Progression and mortality at 10 years.J Neurol Neurosurg Psychiatry. 1999;67: 300-307. Clarke CE, Deane KH. Ropinirole versus bromocriptine for levodopa-induced complications in Parkinson's disease. Cochrane Database Syst Rev. 2001 ;1 :CD001517. Clarke CE, SpellerJM. Pergolide versus bromocriptine For levodopa-induced motor complications in Parkinson's disease. Cochrane Database Syst Rev. 2000;2:CD000236. Rinne UK, Bracco F, Chouza C, et al, for the PKDS009 Study Group. Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. Drugs. 1998;55(SuppI 1):23-30. Barone P, Bravi D, Bermejo-Pareja F, et al, for the Pergolide Monotherapy Study Group. Pergolide monotherapy in the treatment of early PD: A randomized, controlled study. Neurology. 1999;53:573-579. Rascol O, Brooks DJ, Korczyn AD, et al, For the 056 Study Group. A five-year study of-the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N EnglJ Med. 2000;342:14841491. Lieberman AN, Neophytides A, Leibowitz M, et al. Comparative efficacy of pergolide and bromocriptine in patients with advanced Parkinson's disease. Adv Neurol. 1983;37:95-108. Lieberman A, Olanow CW, Sethi K, et al, for the Ropinirole Study Group. A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease [published correction appears in Neurology. 1999;52:435]. Neurology. 1998;51:1057-1062. Pezzoli G, Martignoni E, Pacchetti C, et al. A crossover, controlled study comparing pergolide with bromocriptine

33

Clinical Therapeutics

15.

16.

17.

18.

19.

20.

21.

22.

12

as an adjunct to levodopa for the treatment of Parkinson's disease. Neurology. 1995;45(SuppI 3):$22-$27. Inzelberg R, Nisipeanu P, RabeyJM, et al. Double-blind comparison of cabergoline and bromocriptine in Parkinson's disease patients with motor fluctuations. Neurology. 1996; 47:785-788. Guttman M, for the International Pramipexole- Bromocriptine Study Group. Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. Neurology. 1997; 49:1060-1065. Brunt ER, Brooks DJ, Korczyn AD, et al. A six-month multicentre, doubleblind, bromocriptine-controlled study of the safety and efficacy of ropinirole in the treatment of patients with Parkinson's disease not optimally controlled by L-dopa.J Neural Transrn. 2002;109:489-502. Ziegler M, Castro-Caldas A, Del Signore S, Rascol O. Efficacy of piribedil as early combination to levodopa in patients with stable Parkinson's disease: A 6-month, randomized, placebo-controlled study. Mov Disord. 2003;18:418425. Rascol O, Pathak A, Bagheri H, MontastrucJL. New concerns about old drugs: Valvular heart disease on ergot derivative dopamine agonists as an exemplary situation of pharmacovigilance. Mov Disord. 2004;19: 611-613. Factor SA, Sanchez-Ramos JR, Weiner WJ. Parkinson's disease: An open label trial of pergolide in patients Failing bromocriptine therapy. J Neurol Neurosurg, Psychiatry. 1988;51 : 529-533. Goetz CG, Blasucci L, Stebbins GT. Switching dopamine agonists in advanced Parkinson's disease: Is rapid titration preferable to slow? Neurology. 1999;52:1227-1229. Canesi M, Antonini A, Mariani CB, et al. An overnight switch to ropinirole therapy in patients with Parkinson's

disease.J Neural Transm. 1999;I 06:925929. 23. Castro-Caldas A, Delwaide P, Jost W, et al. The Parkinson-CONTROL study: A I -year randomized, doubleblind trial comparing piribedil (150 mg/day) with bromocriptine (25 mg/day) in early combination with levodopa in Parkinson's disease. Mov Disord. In press. 24. Aguilar M, Delwaide P, Linazasoro G, et al. A double-blind 2-year extension of the Parkinson-CONTROL Study comparing fixed doses of piribedil (150 mg/day) and bromocriptine (25 mg/day)in early combination with L-dopa in Parkinson's disease. Mov Disord. 2005;20(SuppI 10): P259. Abstract. 25. Pezzoli G, Martignoni E, Pacchetti C, et al. Pergolide compared with bromocriptine in Parkinson's disease: A multicenter, crossover, con-

trolled study. Mov Disord. 1994;9: 431-436. 26. Korczyn AD, Brooks DJ, Brunt ER, et al, for the 053 Study Group. Ropinirole versus bromocriptine in the treatment of early Parkinson's disease: A 6-month interim report of a 3-year study. Mov Disord. 1998;I 3: 46-51. 27. Korczyn AD, Brunt ER, Larsen JP, et al, for the 053 Study Group. A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson's disease [published correction appears in Neurology. 1999;53:1162]. Neurology. 1999;53:364-370. 28. Gimenez-Roldan S, Esteban EM, Mateo D. Switching from bromocriptine to ropinirole in patients with advanced Parkinson's disease: Openlabel pilot responses to three different dose-ratios. Clin Neuropkarmacol. 2001 ;24:346-351.

Address correspondence to: St~phane Thobois, MD, PhD, H6pital Neurologique Pierre Wertheimer, Service de Neurologie C (Prof E. Broussolle), 59 Bd Pinel, 69003 Lyon, France. E-maih stephane.thobois@ chu-lyon.fr Volume 28 N u m b e r 1