Role and clinical utility of pramipexole extended release in the treatment of early Parkinson’s disease

Figures & data

Table 1 Pharmacological properties of dopamine agonists

	D2/D3 receptor affinity	D1 receptor affinity	NE receptor affinity	5-HT2B receptor affinity	Half-life (h)
Ergot agonists
Bromocriptine	D2	−	+	+/−	3–6
Cabergoline	D3 > D2	−	+	+	65
Dihydroergocriptine	D2	+/−	+	+	12–16
Lisuride	D2	−	+	+a	2–3
Pergolide	D3 > D2	+	+	+	15–20
Non-ergot agonists
Apomorphine	D3 > D2	+	−	−	0–5
Piribedil	D3 > D2	−	+/–	−	20
Pramipexole	D3 > D2	−	+/–	−	10
Ropinirole	D3 > D2	−	−	−	6
Rotigotine	D3 > D2	+	−	−	5–7b

Notes: −, no affinity; +, high affinity; +/−, moderate affinity.

a Antagonist;

b after transdermal application.

Copyright © 2009, Elsevier. Modified with permission from Antonini A, Tolosa E, Mizuno Y, et al. A reassessment of risks and benefits of dopamine agonists in PD. Lancet Neurol. 2009;8:929–937.⁶

Abbreviation: NE, norepinephrine.

Table 2 Results of the main trials of levodopa versus dopamine agonists in early Parkinson’s disease

	Number on LD (agonist)	Duration (years)	ΔUPDRS part III score		Dyskinesia (% of patients)		Wearing-off (% of patients)
			Levodopa	Agonist	Levodopa	Agonist	Levodopa	Agonist
LD versus ropinirole^Citation8	89 (179)	5	−4.8 ± 8.3	−0.8 ± 10.1	45	20	34	23
LD versus pramipexole^Citation9	151 (150)	2	−7.3 ± 8.6	−3.4 ± 8.6	30.7	9.9	38.0	23.8
LD versus pergolide^Citation10	146 (148)	3	−2.8 ± 7.8	2.8 ± 9.8	26.0	8.2	43.8	30.6

Notes: ΔUPDRS, change in unified Parkinson’s disease rating scale.

* Frequency of motor complications (fluctuations plus dyskinesia).

Copyright © 2009, Elsevier. Modified with permission from Antonini A, Tolosa E, Mizuno Y, et al. A reassessment of risks and benefits of dopamine agonists in PD. Lancet Neurol. 2009;8:929–937.⁶

Abbreviations: LD, levodopa; UPDRS, unified parkinson’s disease rating scale.

Table 3 Efficacy results at week 33 (FAS/LOCF with levodopa rescue censored)

	Placebo (n = 103)	Pramipexole ER (n = 213)	Pramipexole IR (n = 207)
Primary endpoint
UPDRS II + III score, adjusted mean change (95% CI) (P versus placebo, ANCOVA)	−1.2 (−3.1 to 0.6)	−8.2 (−9.5 to −6.9) (<0.0001)	−8.7 (−10.1 to −7.4) (<0.0001)
Key secondary endpoints
CGI-I scale responder rate, % (P versus placebo, CMH)a	20.6	41.4 (0.0003)	45.1 (<0.0001)
PGI-I scale responder rate, % (P versus placebo, CMH)b	16.5	34.4 (0.0008)	32.4 (0.0020)

Notes:

a Proportion of patients classified as either much or very much improved;

b proportion of patients self-classified as either much or very much better.

Copyright © 2011, Wolters Kluwer Health. Modified with permission from Poewe W, Rascol O, Barone P, et al. Extended-release pramipexole in early Parkinson disease: A 33-week randomized controlled trial. Neurology. 2011;77(8):759–766.¹⁷

Abbreviations: FAS, full analysis set; LOCF, last observation carried forward; ER, extended release; IR, immediate release; CMH, Cochran–Mantel–Haenszel test; ANCOVA, analysis of covariance.

Table 4 Rates of successful switching after 9 weeks

Time point	Successfully switched to DB ER	Successfully switched to DB IR	CMH P-value, ER versus IR
4 weeks	84/103 (81.6%)	48/52 (92.3%)	0.0803
9 weeks	87/103 (84.5%)	49/52 (94.2%)	0.0790

Copyright © 2010, John Wiley and Sons. Modified with permission from Rascol O, Barone P, Hauser RA, et al. Efficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson’s disease. Mov Disord. 2010;25(14):2326–2332.²⁰

Abbreviations: DB, double blind; ER, extended release; IR, immediate release; CMH, Cochran–Mantel–Haenszel test.

Table 5 Dosage change from baseline to 9 weeks

	Switched to DB ER			Switched to DB IR
	Dosage increased	Dosage unchanged	Dosage decreased	Dosage increased	Dosage unchanged	Dosage decreased
Entire treatment group	17/103 (16.5%)	83/103 (80.6%)	3/103 (2.9%)	7/52 (13.5%)	44/52 (84.6%)	1/52 (1.9%)
Successfully switched	12/87 (13.8%)	72/87 (82.8%)	3/87 (3.4%)	6/49 (12.2%)	42/49 (85.7%)	1/49 (2.0%)
Not successfully switched	5/16 (31.3%)	11/16 (68.8%)	0/16 (0.0%)	1/3 (33.3%)	2/3 (66.7%)	0/3 (0.0%)

Copyright © 2010, John Wiley and Sons. Modified with permission from Rascol O, Barone P, Hauser RA, et al. Efficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson’s disease. Mov Disord. 2010;25(14):2326–2332.²⁰

Abbreviations: DB, double blind; ER, extended release; IR, immediate release.

Table 6 Frequency of adverse events (%)

	Pramipexole ER	Pramipexole IR	Placebo
Somnolence	20.5	21.4	12.7
Nausea	15.2	15.0	6.6
Constipation	10.5	10.9	3.6
Dyskinesia	9.5	8.6	3.6
Dizziness	6.2	12.7	6.6
Hallucinations	4.3	5.9	0.6
Vomiting	2.4	5.0	1.8

Note: Assessment Report for Sifrol. EMEA/703892/2009.¹⁵

Abbreviations: ER, extended release; IR, immediate release.

AntoniniATolosaEMizunoYYamamotoMPoeweWHA reassessment of risks and benefits of dopamine agonists in Parkinson’s diseaseLancet Neurol200981092993719709931

 PubMed Web of Science ®Google Scholar

RascolOBrooksDKorczynADe DeynPClarkeCLangAA five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study GroupN Engl J Med2000342201484149110816186

 PubMed Web of Science ®Google Scholar

GroupPSPramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study GroupJAMA2000284151931193811035889

 PubMed Web of Science ®Google Scholar

OertelWWoltersESampaioCPergolide versus levodopa monotherapy in early Parkinson’s disease patients: The PELMOPET studyMov Disord200621334335316211594

 PubMed Web of Science ®Google Scholar

PoeweWRascolOBaronePExtended-release pramipexole in early Parkinson disease: A 33-week randomized controlled trialNeurology20117775976621832218

 PubMed Web of Science ®Google Scholar

RascolOBaronePHauserRAEfficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson’s diseaseMov Disord201025142326233220669265

 PubMed Web of Science ®Google Scholar

European Medicines AgencyAssessment Report for Sifrol EMEA/703892/2009LondonEuropean Medicines Agency2009 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000133/WC500049957.pdfAccessed August 9, 2010

 Google Scholar