Pramipexole extended release in Parkinson s disease

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1 For reprint orders, please contact Pramipexole extended release in Parkinson s disease Expert Rev. Neurother. 11(9), (2011) Eva-Maria Hametner 1, Klaus Seppi 1 and Werner Poewe 1 1 Department of Neurology, Innsbruck Medical University, Anichstraße 35, A-6020 Innsbruck, Austria Author for correspondence: Tel.: Fax: werner.poewe@i-med.ac.at Pramipexole extended release (ER) is a new once-daily formulation of pramipexole, a nonergot dopamine agonist, which is available in five dosage strengths: 0.26 (0.375) mg, 0.52 (0.75) mg, 1.05 (1.5) mg, 2.1 (3) mg and 3.15 (4.5) mg (all doses are expressed in terms of pramipexole base and the corresponding dose strengths of pramipexole salt are given in brackets). Pramipexole ER is currently approved as monotherapy in early Parkinson s disease (PD), as well as an adjunct therapy to levodopa in advanced PD. Compared with the immediate release (IR) formulation, the ER formulation offers several advantages, including the potential for improved compliance owing to its simple once-daily dosing regimen and steadier plasma levels over 24 h. Doubleblind, randomized, placebo and active comparator controlled trials in early, as well as advanced PD, established the superiority of both pramipexole ER and IR over placebo. The overnight switch from pramipexole IR three times a day to ER once-daily in early PD has been shown to be successful in more than 80% of patients. Pramipexole ER is well tolerated, with a similar adverse event profile to pramipexole IR. The aim of this article is to provide a short review of the most relevant pharmacological and clinical data on pramipexole ER. Keywords: dopamine agonist once-daily formulation Parkinson s disease PD treatment pramipexole pramipexole ER pramipexole extended release pramipexole/pharmacodynamics pramipexole/pharmacokinetics Parkinson s disease (PD) is a chronic progressive, neurodegenerative movement disorder characterized by the cardinal motor features brady kinesia, rigidity, resting tremor and postural instability. After Alzheimer s disease, PD is the second most common neurodegenerative disease, with both incidence and prevalence rates increasing with age. Levodopa is still the most effective treatment to improve the motor symptoms of PD. However, its chronic use is associated with the development of motor fluctuations and dyskinesias. Initial monotherapy with dopamine agonists is associated with lower rates of motor complications compared with levodopa [1 5]. Overview of the market In the 1970s, the first oral dopamine agonist, bromocriptine, was introduced for the treatment of PD. Dopamine agonists exert their symptomatic antiparkinsonian effect through direct stimulation of presynaptic (autos) and postsynaptic dopamine s, with preferential for the D2 subfamily of dopamine s (Table 1). Large randomized levodopa-controlled trials with different dopamine agonists, including cabergoline [1], pergolide [2], pramipexole [3,4] and ropinirole [5] have demonstrated significantly reduced risk of motor complications, especially dys kinesias, compared with treatment initiation with levodopa, but symptomatic effect sizes based on the Unified Parkinson s Disease Rating Scale (UPDRS) [6] were less than those seen with levodopa. Side effects, including hallucinations, daytime somnolence and sudden onset of sleep, as well as impulse control disorders, are more frequently seen with dopamine agonist treatment [7]. Nevertheless, many national and international guidelines [8,9] suggest dopamine agonists as the first-line option for initial monotherapy in early PD, particularly in patients with young-onset parkinsonism, who are at high risk for levodopainduced dyskinesias. In addition, adjunct therapy with dopamine agonists is a first-line option to reduce levodopa related motor fluctuations in advanced PD. Several different formulations of dopamine agonists are currently available, including immediate release (IR) and extended release (ER) tablets for oral administration (ropinirole, pramipexole, cabergoline, peripedil, pergolide and bromocriptine) and transdermal patches (rotigotine), as well as subcutaneous applications (apomorphine) for intermittent or continuous use /ERN Expert Reviews Ltd ISSN

2 Hametner, Seppi & Poewe Table 1. Pharmacological properties of dopamine agonists. Dopamine agonists Ergot agonists D2/D3 D1 NE Introduction to the agent/pharmacodynamics Pramipexole is an aminobenzothiazole compound representing a full intrinsic dopamine agonist with a nonergot structure. Pramipexole ER is available in five dosage strengths: 0.26 (0.375), 0.52 (0.75), 1.05 (1.5), 2.1 (3) and 3.15 (4.5) mg (all doses are expressed in terms of pramipexole base and the corresponding dose strengths of pramipexole salt are given in brackets), and it is approved for use in early PD, as well as an adjunct therapy in advanced PD with motor complications. Pramipexole shows high selectivity for the D2 family, with preferential for the D3 subtype [10]. There is lower for D2 and D4 subtypes and the agent lacks for dopamine s D1 and D5 [11]. Its structure is illustrated in Figure 1. Pharmacokinetics & metabolism Pramipexole ER a matrix single-unit prolonged release tablet releases pramipexole dihydrochloride monohydrate, which is dispersed homogenously throughout the matrix, by the two different mechanisms of diffusion and erosion. Following oral administration gastrointestinal fluids penetrate the matrix and dissolve the 5-HT 2B Bromocriptine D /- 3 6 Cabergoline D3 > D Half-life (h) Dihydroergocriptine D2 +/ Lisuride D Pergolide D3 > D Nonergot agonists Apomorphine D3 > D Piribedil D3 > D2 - +/ Pramipexole D3 > D2 - +/ Ropinirole D3 > D Rotigotine D3 > D Antagonist. After transdermal application. -: No ; +: High ; +/-: Moderate ; 5-HT: 5-hydroxytryptamine; NE: Norepinephrine. Modified from [28]. H 2 N N S H N C 10 H 21 Cl 2 N 3 OS 2 HCl H 2 O Figure 1. Sifrol (pramipexole dihydrochloride monohydrate). active substance. The erosion mechanism directly separates the matrix surface from the core and thus leads to direct release of the active substance. The in vitro release characteristics of the active substance are proportional to the square-root of time [101]. In other respects, the pharmacokinetic profile of pramipexole ER is similar to the IR formulation. Concomitant intake of a highfat meal was shown to result in an increase of C max. After oral administration the agent is completely absorbed, showing an absolute bioavailability of >90% [101]. In contrast to the IR formulation, the maximum plasma concentration is reached later, approximately 6 h following oral administration (IR: C max 1 3 h). In humans, the protein binding of pramipexole is very low (<20%). Pramipexole is only metabolized to a small extent and the major route of elimination is renal excretion of unchanged pramipexole (~90%). As the drug is not metabolized by the cytochrome P450 enzyme system, it is not anticipated to have deleterious effects on the hepatic metabolism of concomitant medications [12]. The renal clearance of pramipexole is approximately 400 ml/min and the elimination half-life (t ½ ) varies from 8 h in the young to 12 h in the elderly. Clinical efficacy Phase I Clinical trials in healthy male volunteers were conducted to evaluate the pharmacokinetic and pharmacodynamic properties of pramipexole ER [13]. Initially, seven prototypes of a once-daily ER formulation (0.52 [0.75] mg once-daily) with various release properties, including rate and ph dependence, were compared with the IR formulation (0.18 [0.25] mg three times a day) to identify the optimal pharmacokinetic resemblance. The optimal pharmacokinetic resemblance was defined as AUC 0 24h >75% of pramipexole IR. Among the seven prototypes a matrix tablet demonstrated optimal characteristics, showing a geometric mean AUC 0 24 h of 17.4 (ER) versus 16.0 ng h/ml (IR). A single-dose pharmacokinetic study, which was aiming to predict the entire in vivo bioavailability time course based on in vitro dissolution, satisfied the current guidelines of a level A in vitro/in vivo correlation [102], revealing internal mean absolute prediction errors of 3.18% for AUC 0 30 h and 4.87% for C max. External analyses showed analogous results (AUC 0 30 h : 6.61%; C max : 3.34%). Steady-state pharmacokinetics were assessed, including the investigation of food effects and dose proportionality. Dosing at 0.26 (0.375) mg to 3.15 (4.5) mg in the fasted state was found to be associated with a linear, dose-proportionate increase in the pharmacokinetic parameters AUC 0 24 h and C max and met the criteria for bioequivalence with the IR formulation. Concomitant intake of a high-fat meal did not significantly affect AUC 0 24 h, but 1230 Expert Rev. Neurother. 11(9), (2011)

3 Pramipexole extended release in Parkinson s disease Drug Profile induced an increase in C max of approximately 24% after a single dose administration and of approximately 20% after multiple dose administrations [13,101]. Phase II No Phase II studies were performed. Phase III Early PD A 33-week, randomized, double-blind, placebo-controlled, parallel group study was conducted to evaluate superiority of efficacy of pramipexole ER to placebo (18-week results), as well as to demonstrate noninferiority of pramipexole ER to pramipexole IR (33-week results) [14]. Patients with PD at Hoehn and Yahr stage 1 3 [15] diagnosed within the preceding 5 years were randomized (2:2:1) to receive pramipexole ER ( [ ] mg once-daily), pramipexole IR ( [ ] mg three times a day) or placebo. After randomization all subjects entered a 7-week flexible uptitration phase, followed by a 26-week maintenance period, during which open-label levodopa rescue medication was permitted for subjects experiencing insufficient control of parkinsonism in order to maximize patient retention in the trial. Post-levodopa rescue data were censored for the primary ana lysis. For blinding purposes a double-dummy medication design was employed (each patient received four treatments per day). The primary efficacy end point in the two coprimary analyses of efficacy was change in the combined score on UPDRS [6] Part II (activities of daily living) and Part III (motor function). Noninferiority was predefined as a treatment-group difference for which the lower bound of the 95% CI did not exceed -3 points. This margin had been chosen conservatively to be well outside the minimally clinically relevant difference on the UPDRS, which has been suggested to be -7 points for combined Parts II and III [16]. Secondary outcome measures included Clinician Global Impression of Improvement (CGI-I) score [17], Patient Global Impression of Improvement (PGI-I) [17], UPDRS [6] II + III responder rates (predefined as 20% improvement from baseline score), proportions of patients requiring levodopa rescue, as well as quality of life scales. At 18 weeks, the adjusted mean change in UPDRS [6] II + III combined scores, censoring post-levodopa rescue data, was -7.4 (1.1) in the pramipexole ER group, compared with -2.7 (1.3) in the placebo group (p = vs placebo) and -7.5 (1.1) in the pramipexole IR group (p = vs placebo). Including data from subjects receiving levodopa rescue medication, the adjusted mean change was -5.1 (1.3) for placebo, -8.1 (1.1) for pramipexole ER (p = vs placebo) and -8.4 (1.1) for pramipexole IR (p = vs placebo). Hence, using either approach, a statistically significant difference between pramipexole groups and placebo could be demonstrated from week 4 onward (ER: p = ; IR: p = vs placebo at week 4 by either approach). The results of secondary end points are given in Table 2. At 33 weeks the UPDRS [6] II + III change, censoring postlevodopa-rescue data, was -8.2 for ER and -8.7 for IR. The resultant treatment difference was -0.5 (95% CI: -2.3 to +1.3), thereby establishing noninferiority of the ER formulation. Including levodoparescue data, the adjusted mean decrease was -8.5 versus -9.4, revealing a difference of -0.9 (95% CI: -2.7 to 0.9), which is still well within the predefined margin. As already demonstrated at 18 weeks, the 33-week ana lysis confirmed superiority of pramipexole ER over placebo (adjusted mean change in UPDRS [6] II + III score: -8.2 ER vs -1.2 placebo [p < ]). Consistent with the symptomatic efficacy of pramipexole, fewer patients on active treatment required levodopa rescue medication (7.0% ER, 4.3% IR and 21.4% placebo). Superiority of both pramipexole formulations could also be shown for CGI-I [17] responder rates (41.4% ER, 45.1% IR vs 20.6% placebo [p = and p < ]), PGI-I [17] responder rates (34.4% ER, 32.4% IR vs 16.5% placebo [p = and p = ]) and UPDRS II + III [6] responder rates (66.7% ER, 63.8% IR vs 35.0% placebo [p < ]). Advanced PD A total of 507 patients with advanced PD, defined as Hoehn and Yahr stage 2 4 and motor fluctuations ( 2 h of daily off-time), provided postbaseline data for the study s 18-week efficacy analyses [18]. The primary efficacy outcome measure was defined as change in combined score of UPDRS [6] II (averaged for on- and off-time) + III (assessed during on-time) from baseline to week 18. The key secondary end point was change in diary-determined daily off-time. Further secondary end points included change in daily on-time and responder rates on the CGI [17] and PGI-I [17] scales, as well as UPDRS [6] II+III responder rates (defined by 20% improvement from baseline score). Following randomization (1:1:1), dosages were optimized during a 7-week flexible titration phase and then remained stable for 11 weeks. The mean final pramipexole dosage was comparable in both active treatment groups (1.44 mg/day ER and 1.42 mg/day IR). To maintain double-blinding, all patients received four treatments (pramipexole Table week results of secondary end point measures (levodopa data censored). Secondary end point measures (levodopa data censored) Pramipexole ER, % UPDRS II + III responder rate 67.6 (p = ) PGI-I responder rate 35.6 (p = ) CGI-I responder rate 37.0 (p = ) Pramipexole IR, % Placebo, % 69.3 (p < ) 23.8 (p = ) 48.0 (p = ) Proportion of patients with 20% improvement from baseline score. Proportion of patients self-classified as either much or very much better. Proportion of patients classified as either much or very much improved. CGI-I: Clinical Global Impression-Improvement scale; ER: Extended release; IR: Immediate release; PGI-I: Patient Global Impression-Improvement scale; UPDRS: Unified Parkinson s Disease Rating Scale. Data taken from [15]

4 Hametner, Seppi & Poewe ER or placebo) per day. At week 18 the decrease in UPDRS [6] Part II+III score was significantly greater in both pramipexole groups (ER and IR -12.8), compared with placebo (-6.1; p = and p < ). Daily off-time showed a decrease of -2.1 h per day (h/d) for pramipexole ER and -2.5 h/d for pramipexole IR, versus -1.4 h/d for placebo (p = and p < ). After 18 weeks, superiority of pramipexole ER over placebo was demonstrated. This result was corroborated by the maintained improvement on UPDRS [6] II + III and in daily proportion of off-time, which was descriptively shown among 208 patients completing 33 weeks ( 10.1% change from 18-week results). Switch Study The Switch Study [19] was designed as a double-blind, doubledummy, randomized, parallel-group study to assess the overnight switch of early PD patients from pramipexole IR to ER formulation. After a 2 4-week open-label run on pramipexole IR three times a day, 156 patients were switched overnight to either ER or IR at an unchanged daily dosage (randomized 2:1). At week 4 and 5 dose adjustments, in terms of a one-step increase or decrease, were allowed as required for efficacy and/or tolerability. Doses had to be kept stable for the final 4 weeks of the trial. The primary efficacy end point was defined as the proportion of patients successfully switched at the end of week 9, which was defined as no worsening from baseline UPDRS [6] II + III score by >15% and no withdrawal due to drug related adverse events. Noninferiority was predefined as a 95% CI with a lower bound not exceeding -15%. After 9 weeks 84.5% of the patients in the ER group and 94.2% in the IR group had been successfully switched. Hence, noninferiority of pramipexole ER was not formally demonstrated (in between-group difference -9.8% [CI: 95%: ]), and likewise pramipexole IR was not formally superior to pramipexole ER because the 95% CIs included zero. Overall, at 9 weeks, 80.6% of patients in the ER group and 84.6% in the IR group were successfully switched without requiring any dose adjustments. In the ER group, 16.5% had increased and 2.9% had decreased their dosage, while corresponding percentages in the IR group were 13.5 versus 1.9%. The between-group difference for increased versus unchanged/decreased dosage was not significant (p = ). The mean pramipexole dosage at 9 weeks was 2.75 (±0.95) mg/day (+0.12 mg/day from baseline) in the ER group compared with 2.83 (±0.86) mg/day (+0.09 mg/day from baseline). In terms of safety and tolerability, this study revealed similar AE rates in subjects switched to pramipexole ER (36.5%) and subjects who remained on pramipexole IR (30.8%). Safety & tolerability Overall, 803 PD patients were exposed to clinically effective doses of pramipexole ER in the clinical trial program, corresponding to approximately 180 patient-years for safety evaluation. Pooled safety data of the clinical trials in early and advanced PD show a slightly higher rate of adverse events in both pramipexole groups compared with placebo and no significant difference in adverse event profiles between both pramipexole formulations. The most common side effects are given in Table 3 [101]. According to the results of the 33-week trial in early PD patients [14], the most frequent adverse events were somnolence, gastrointestinal complaints and dizziness. In this study, a small numerical increase in Epworth Sleepiness Scale score was observed in both pramipexole groups, but mean values remained below the cutoff for excessive daytime sleepiness ( 10). Impulse control disorders were also slightly more common in both active treatment groups (four patients in the ER, three in the IR and one in the placebo group). In advanced PD with concomitant levodopa treatment, the incidence of specific events after 18 weeks did not differ by more than 3% between the ER and IR groups except for dizziness (4.9 vs 10.3%) and vomiting (1.2 vs 5.7%), which were reported by fewer patients in the ER group. Anorexia was more frequent among patients in the ER group (4.9 vs 1.1%). Overall, pramipexole ER showed the same safety and tolerability profile that has already been established for pramipexole IR. Conclusion & expert commentary The nonergot dopamine agonist pramipexole is an established firstline drug for the treatment of both early and advanced PD. After successful bioequivalence testing, its novel ER formulation has been shown to offer identical symptomatic control as the standard IR formulation when given as initial monotherapy in early PD or when administered as an adjunct to levodopa in patients with motor fluctuations in two large pivotal trials. The major clinical advantage of the new ER formulation is clearly related to its ease of use and patient convenience, which we speculate, may ultimately translate into improved compliance and adherence compared to pramipexole IR [20 22]. Indeed, this potential advantage was not studied in the pivotal trial program, owing to the double-dummy approach, which had to be used for blinding purposes [14,18,19]. However, it is well documented that drug adherence worsens as the number of doses per day increase [21,23]. A recent multicenter study has shown not only worse motor control in PD patients when they missed over 20% of prescribed doses but also worse fluctuations when their medication intake occurred at varying time intervals. The same study found that once-daily drugs, including cabergoline, rasagiline and selegiline, were more likely to be taken correctly by all measures of therapy adherence, compared to drugs prescribed more frequently [21]. In practical terms, the available trial data also indicate that patients on IR pramipexole can be switched to the ER formulation at identical doses in a one-step overnight procedure, although a minority may need dose adjustments [19]. An issue that remains worth being addressed in future studies, is the possibility of improved tolerability, particularly pertaining rates of nausea, orthostatic hypotension or even somnolence, owing to the ER design, which avoids multiple plasma level peaks over the day. Five-year view Optimizing dopaminergic drug delivery in PD has been a notoriously difficult issue ever since the introduction of levodopa [24]. Efforts continue to provide more constant levodopa delivery, but so far attempts using slow-release formulations or dual enzyme inhibition with decarboxylase and COMT-inhibitors have been of limited success and have not reduced pill burden [25] Expert Rev. Neurother. 11(9), (2011)

5 Pramipexole extended release in Parkinson s disease Drug Profile Duodenal delivery is invasive and cumbersome [26], while transdermal approaches have been met with difficulties of poor skin absorption [27]. On the other hand, dopamine agonists have several advantages including their longer half-life and the successful development of slow-release formulations or transdermal patches [28]. Their current major limitation is related to reduced efficacy compared with levodopa and the increased burden of potentially serious side effects, including daytime somnolence, sleep attacks and impulse control disorders [28]. Nevertheless, in a current dopamine agonist market once-daily ER formulations will be an attractive option for many patients minimizing pill burden for initial monotherapy in de novo cases and contributing to enhanced symptom control and reduced motor fluctuations throughout the day in patients with advanced disease and levodopa-related motor complications. Information resources Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe W. A reassessment of risks and benefits of dopamine agonists in Parkinson s disease. Lancet Neurol. 8(10), (2009). Boehringer Ingelheim: European Medicines Agency (EMEA): Financial & competing interests disclosure Klaus Seppi has received honoraria for speaking and/or consulting from Novartis, AstraZeneca, Boehringer Ingelheim, Lundbeck, Schwarz Pharma, UCB Pharma, Teva and GlaxoSmithKline, and grants/research funding Table 3. Frequency of adverse events. Adverse events Pramipexole ER (%) Pramipexole IR (%) Placebo (%) Somnolence Nausea Constipation Dyskinesia Dizziness Hallucinations Vomiting ER: Extended release; IR: Immediate release. Modified with permission from [101]. from The Movement Disorders Society, Michael J Fox Foundation for Parkinson s Research, Österreichische Nationalbank, Austrian Science Fund (FWF) and Medical University Innsbruck. Werner Poewe has received consultancy and lecture fees from AstraZeneca, Teva, Novartis, GlaxoSmithKline, Boehringer-Ingelheim, UCB, Orion Pharma and Merck Serono in relation to clinical drug development programs for PD, and grants/research funding from The Movement Disorders Society, Michael J Fox Foundation for Parkinson s Research, Österreichische Nationalbank, Austrian Science Fund (FWF) and Medical University Innsbruck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Key issues Pramipexole extended release (ER) is a new once-daily formulation of the nonergot dopamine agonist pramipexole. Pramipexole ER has demonstrated noninferiority compared with pramipexole immediate release (IR) in the treatment of early and advanced Parkinson s disease. The overnight switch of early Parkinson s disease patients from pramipexole IR three times a day to pramipexole ER once daily has been shown to be successful in more than 80% of patients. Pramipexole ER is well tolerated and has a similar adverse-event profile to pramipexole IR. References 1 Bracco F, Battaglia A, Chouza C et al. The long-acting dopamine agonist cabergoline in early Parkinson s disease: final results of a 5-year, doubleblind, levodopa-controlled study. CNS Drugs 18(11), (2004). 2 Oertel W, Wolters E, Sampaio C et al. Pergolide versus levodopa monotherapy in early Parkinson s disease patients: the PELMOPET study. Mov. Disord. 21(3), (2006). 3 Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Parkinson Study Group. JAMA 284(15), (2000). 4 Holloway R, Shoulson I, Fahn S et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch. Neurol. 61(7), (2004). 5 Rascol O, Brooks D, Korczyn A, De Deyn P, Clarke C, Lang A. A five-year study of the incidence of dyskinesia in patients with early Parkinson s disease who were treated with ropinirole or levodopa. 056 Study Group. N. Engl. J. Med. 342(20), (2000). 6 Fahn S, Elton R. The Unified Parkinson s Disease Rating Scale. In: Recent Developments in Parkinson s Disease Volume 2. Fahn S, Marsden CD, Caine BD, Goldstein M (Eds). Macmillan Healthcare Information, NJ, USA, , (1987). 7 Stowe R, Ives N, Clarke C et al. Dopamine agonist therapy in early Parkinson s disease. Cochrane Database Syst. Rev. 2, CD (2008). 8 Horstink M, Tolosa E, Bonuccelli U et al. Review of the therapeutic management of Parkinson s disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late (complicated) Parkinson s disease. Eur. J. Neurol. 13(11), (2006). 9 Miyasaki J, Martin W, Suchowersky O, Weiner W, Lang A. Practice parameter: initiation of treatment for Parkinson s disease: an evidence-based review: report of

6 Hametner, Seppi & Poewe the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 58(1), (2002). 10 Gerlach M, Double K, Arzberger T, Leblhuber F, Tatschner T, Riederer P. Dopamine agonists in current clinical use: comparative dopamine binding profiles defined in the human striatum. J. Neural Transm. 110(10), (2003). 11 Kohno Y, Takeuchi S. [Pharmacological profiles and clinical effects of antiparkinsonian agent, pramipexole]. Nippon Yakurigaku Zasshi 123(6), (2004). 12 Wynalda M, Wienkers L. Assessment of potential interactions between dopamine agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab. Dispos. 25(10), (1997). 13 Jenner P, Könen-Bergmann M, Schepers C, Haertter S. Pharmacokinetics of a once-daily extended-release formulation of pramipexole in healthy male volunteers: three studies. Clin. Ther. 31(11), (2009). 14 Hauser RA, Schapira AH, Rascol O et al. Randomized, double-blind, multicenter evaluation of pramipexole extended release once daily in early Parkinson s disease. Mov. Disord. 25(15), (2010). 15 Hoehn M, Yahr M. Parkinsonism: onset, progression and mortality. Neurology 17(5), (1967). 16 Schrag A, Spottke A, Quinn N, Dodel R. Comparative responsiveness of Parkinson s disease scales to change over time. Mov. Disord. 24(6), (2009). 17 Guy W. Clinical Global Impressions. ECDEU Assessment Manual for Psychopharmacology. NIH, MD, USA (1976) 18 Schapira A, Barone P, Hauser R et al. Efficacy and safety of pramipexole extended-release for advanced Parkinson s disease. In: Proceedings of the 13th Annual International Congress of Parkinson s Disease and Movement Disorders. Poster WE-199 (2009). 19 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. 25(14), (2010). 20 Leopold N, Polansky M, Hurka M. Drug adherence in Parkinson s disease. Mov. Disord. 19(5), (2004). 21 Grosset D, Antonini A, Canesi M et al. Adherence to antiparkinson medication in a multicenter European study. Mov. Disord. 24(6), (2009). 22 Grosset K, Bone I, Grosset D. Suboptimal medication adherence in Parkinson s disease. Mov. Disord. 20(11), (2005). 23 Claxton A, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin. Ther. 23(8), (2001). 24 Nyholm D, Askmark H, Gomes-Trolin C et al. Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets. Clin. Neuropharmacol. 26(3), (2003). 25 Goetz C, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson s disease: 2001 to Mov. Disord. 20(5), (2005). 26 Valldeoriola F, Cámara A. [Intraduodenal infusion of levodopa]. Rev. Neurol. 51(1), (2010). 27 Reichmann H. Transdermal delivery of dopamine agonists. Parkinsonism Relat. Disord. 15(Suppl. 4), S93 S96 (2009). 28 Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe WH. A reassessment of risks and benefits of dopamine agonists in Parkinson s disease. Lancet Neurol. 8(10), (2009). Websites 101 Assessment Report for Sifrol. (European Medicines Agency) EMEA/703892/ document_library/epar_-_assessment_ Report_-_Variation/human/000133/ WC pdf 102 Guidance for industry. Extended release oral dosage forms: development, evaluation and application of in vitro/in vivo correlations (US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research, September 1997) GuidanceComplianceRegulatory Information/Guidances/ucm pdf 1234 Expert Rev. Neurother. 11(9), (2011)

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