Rotigotine transdermal patch in the management of Parkinson s disease (PD) and its night-time use for PD-related sleep disorders

Transcription

1 Rotigotine transdermal patch in the management of Parkinson s disease (PD) and its night-time use for PD-related sleep disorders Angelo Antonini, MD, PhD a,b,c Laura Bernardi, MD a Daniela Calandrella, MD, PhD c Francesca Mancini, MD, PhD c Mauro Plebani, MD a a Department for Parkinson s disease, IRCCS San Camillo, Venice, Italy b University of Padua, Italy c San Pio X Hospital, Milan, Italy Corresponding author: Angelo Antonini Parkinson s Disease Department IRCCS San Camillo Via Alberoni 60, Venice Lido, Italy angelo3000@yahoo.com Summary Rotigotine (Neupro ) is a non-ergolinic dopamine agonist available as a transdermal patch that can be applied once daily. To date, it is approved as monotherapy for the treatment of early Parkinson s disease (PD), and as adjunctive therapy to levodopa in the treatment of PD, including the advanced stage of the disease, when the efficacy of levodopa is reduced or becomes inconsistent and there are fluctuations in the therapeutic effect (end-dose, ON-OFF phenomenon). The potential advantages of the rotigotine patch include immediacy of effect onset as intestinal absorption is not needed, constant drug delivery, and ease of use. This review provides an overview of several aspects of the use of the rotigotine transdermal patch, including the important issue of the management of sleep disorders in advanced PD patients, as well as the chemistry, preclinical and clinical pharmacology, efficacy, safety and tolerability of the drug. Furthermore, the rationale for the treatment of PD with the rotigotine transdermal patch is discussed, focusing in particular on the related sleep disorders. KEY WORDS: Parkinson s disease, rotigotine, sleep, quality of life Introduction Parkinson s disease (PD) is a progressive degenerative disorder that affects every race and culture, with a prevalence of about 3% in the general population. It is the second most common neurological cause of disability and has a major and increasing impact on quality of life (1). Psychiatric, cognitive and sleep disorders are the most frequent and disabling non-motor complications of PD. Indeed, around 60% of PD patients report sleep disorders which include frequent awakenings, daytime sleepiness, altered dream phenomena, and REM sleep behaviour disorder (RBD), even during combined oral dopaminergic therapy with levodopa and dopamine agonists. Some authors have suggested that these phenomena could even precede the onset of motor symptoms (2). The disease is otherwise clinically characterized by the cardinal motor features of tremor, rigidity and bradykinesia (3) and pathologically by neuronal loss in the substantia nigra and other brainstem nuclei (4) and by the presence of Lewy bodies (ubiquinated protein deposits in the cytoplasm of neurons) and Lewy neurites (thread-like proteinaceous inclusions within neurites) (5). The classic clinical symptoms of the disease are caused by loss of dopamine resulting from degeneration of dopamine-producing cells in the substantia nigra (4). Levodopa remains the most effective treatment for the motor symptoms of the disease but it can produce minor complications such as fluctuations and dyskinesias after approximately five years of therapy (6). The majority of drugs available for the treatment of PD are for oral use. Oral administration offers convenience but the processing through the gastrointestinal tract and the first pass metabolism via the liver can make the response and the dosing schedule difficult to optimize. Many of the oral drugs, due to their short duration of action, need frequent dosing and hence promote pulsatile dopaminergic stimulation of neurons. To overcome this, controlled release oral formulations, drug combination tablets, parenterally administered drugs, transdermal formulations and drug delivery direct to the lower gastrointestinal tract have been used. Eight different marketed molecules make up the dopamine agonist class and half of these fall into the frequent schedule treatments described above. Once-daily treatments are carbergoline, which can be associated with ergolinic side effects, and apomorphine, which can be administered subcutaneously but comes with administration limits that preclude its widespread use. Ropinirole has been approved with an extended release formulation for once-daily use, and an extended release formulation of pramipexole is being developed. Continuous drug delivery such as that provided by transdermal systems can yield steady plasma levels that have been shown to provide constant receptor stimulation which may reduce the appearance of PD motor complications and sleep disorders. This new administration route became established with the approval of the rotigotine transdermal patch for clinical use, and it has opened up new possibilities for the treatment of PD and for the study of the efficacy of dopaminergic continuous delivery systems (7). Functional Neurology 2010; 25(1):

2 A. Antonini et al. Pharmacokinetic profile The earliest studies conducted with the aminotetralin derivate N-0437 led to the development of the (-)-enantiomer of N0437 which became known as N-0923, and later as rotigotine (8). In early trials, the aminotetralin derivate N-0437 proved to have only a short duration of effect following oral administration but a significantly prolonged effect after transdermal application (9). Nowadays, due to its extensive gastrointestinal metabolism, rotigotine is available only for transdermal drug delivery as a patch (10). It has been designed as a matrix-type transdermal system and consists of a backing film, a drug-loaded matrix, and a protective liner (11). The patch, applied to intact skin, releases the active substance continuously over 24 hours through transcellular, intercellular, follicular, and eccrine routes; thus, lipophilic and hydrophilic penetration is achieved. Rotigotine drug delivery has been shown to be proportional to patch size and patches releasing 2 mg, 4 mg, 6 mg, and 8 mg of rotigotine per 24 hours are now available. For patients with early-stage PD, an initial dose of 2 mg/24 h can be increased by weekly increments of 2 mg/24 h to reach a maximum dose of 8 mg/24 h. For patients with advanced-stage PD and motor fluctuations, an initial dose of 4 mg/24 h can be increased by 2 mg/24 h weekly increments up to a maximum dose of 16 mg/24 h. For doses over 8 mg/24 h, multiple patches must be applied. No dose adjustment for age, gender, weight, or mild-to-moderate renal or hepatic impairment is necessary (8). Mechanism of action and selectivity Rotigotine is a non-ergolinic dopamine receptor agonist that is thought to exert its antiparkinsonian effect through activation of the dopamine receptors D1, D2, and D3 in the caudate putamen. Rotigotine has agonist effects on all the dopamine receptors showing greatest affinity for, and activity at, the D3 receptor subtype. Rotigotine has negligible affinity for 5-HT 2B receptors. In addition to the selectivity described above, a slow release formulation of rotigotine generated constant extracellular drug levels in the brains of freely-moving rats following subcutaneous administration; these levels were maintained for at least 48 hours and were accompanied by a concomitant and maintained reduction in extracellular dopamine to about 20% of vehicle control levels (12). As dopamine synthesis is controlled by presynaptic receptors this observation supports the suggestion that rotigotine has the potential to induce continuous stimulation of dopamine receptors. Preliminary evidence in animal models indicates that a reduction in parkinsonian symptoms in rotigotine-treated animals correlates with a partial protection of dopamine terminals using ex vivo DAT labeling (13,14). Clinical pharmacology Laboratory and clinical studies have demonstrated uniform rotigotine release from the entire surface of the transdermal system. The amount of rotigotine released was generally constant over 24 hours and was proportional to the patch surface area (15). Absorption per square centimeter did not differ between patients with PD and healthy volunteers (16). Rotigotine and its metabolites are widely distributed into tissues (16). The weight-normalized apparent volume of distribution is 84L/kg with 89.5% plasma protein binding in vivo. Rotigotine is a high-clearance drug (630 L/h) and is extensively metabolized (17). The principal metabolites of rotigotine are sulfate and glucuronide conjugates of the parent compound, as well as N-desalkyl metabolites, which are biologically inactive (16). Approximately 71% of a rotigotine dose is excreted in the urine as conjugates of rotigotine and its N-desalkyl metabolites, and approximately 23% is excreted in the feces (16). The rotigotine plasma concentration time course after patch removal was best described by a two-compartment model (18). In 20 volunteers, rotigotine elimination showed a biphasic pattern, with an initial half life of 2 to 3 hours and a terminal elimination t1/2 of 10 to 20 hours. (18). Rotigotine appears to have a low drug interaction potential (19). Efficacy The clinical efficacy of transdermal rotigotine as monotherapy and as adjunctive therapy to levodopa has been evaluated in patients with early-stage and advanced PD. Sleep disorders in advanced Parkinson s disease Since PD patients with motor fluctuation frequently complain of sleep disorders, even during combined oral dopaminergic therapy with levodopa and dopamine agonists, a study (20) was conducted to assess the benefit of night-time rotigotine on sleep evaluated with the Parkinson s Disease Sleep Scale (PDSS). Ten non-demented PD patients with disease duration ranging between eight and 14 years (mean 10.4±5 yrs) and aged years (mean 68.2±8 yrs) were studied. All patients were on oral levodopa therapy (740±250 mg). Six patients were on oral pramipexole (average dose 2.5 mg) and four were on ropinirole extended release formulation taken as a morning dose (average dose 12 mg). Duration of daily OFF time was less than three hours in all patients. The PDSS score was 88.0±12.2 at baseline. In all cases rotigotine was added to all other medications and assessed after one month of therapy (Fig. 1). All patients wore a rotigotine patch from 10 pm to 8 am. The rotigotine dose was titrated to reach a range of between 4 and 8 mg. No adverse events were observed. The mean PDSS score improved to ±19.75 after four weeks of therapy. Six patients reported a subjective improvement (Fig. 2). The authors concluded that adding a night-time rotigotine patch improves sleep problems in advanced PD patients. Early Parkinson s disease A phase II dose escalation study of rotigotine monotherapy in early PD examined symptom control as a secondary variable (21). The majority of patients (83%) were maintained at a rotigotine dose of 8 mg/24 h, the maxi- 22 Functional Neurology 2010; 25(1): 21-25

3 Rotigotine for the management of night-time PD problems mum dose allowed in this study (21). Three large-scale placebo-controlled phase III studies of rotigotine in early PD assessed efficacy as a primary outcome measure. In a US/Canadian study, the Parkinson Study Group reported significant improvements from baseline in combined UPRDS ADL/motor scores for rotigotine doses of 6 mg/24 h (-5.09; p=0.001) and 8 mg/24 h (-5.30; p<0.001), in comparison with placebo (-0.29) (15). This significant effect was apparent from week 4, while a return towards baseline was observed immediately after medication withdrawal at week 11 (15). A second placebo-controlled phase III study of rotigotine in early PD examined efficacy over a longer duration: 27 weeks (22,23). In this study rotigotine ( 6 mg/24 h) produced a 5.3-point improvement in the combined UPDRS ADL/motor score versus placebo (p<0.0001), with the UPDRS motor score making the greatest contribution to this improvement (22,23). In addition, there was a significantly higher proportion of responders ( 20% decrease from baseline in UPDRS score) in the rotigotine versus the placebo group (48% vs 19%; p<0.001) and this was associated with an improvement in quality of life (22). In a third phase III study, the efficacy of rotigotine in early PD was compared with that of ropinirole over a ~ 37- week period (24). The proportion of responders ( 20% reduction in combined UPDRS ADL/motor score) was significant for both rotigotine 8 mg/24 h (52%) and ropinirole 24 mg/day (68%), versus placebo (30%; p<0.0001) (24). Significant improvements in absolute mean decreases from baseline were also observed in combined UPDRS ADL/motor scores for rotigotine (-7.2), and ropinirole (-11.0), versus placebo (-2.2; p<0.0001) (24). Together, these phase III study results support the efficacy of rotigotine monotherapy versus placebo in the treatment of early PD. Advanced Parkinson s disease The efficacy of transdermal rotigotine as adjunctive therapy to levodopa in patients with advanced PD has been evaluated in two large randomized, double-blind, multicenter phase III studies. Both studies were placebo-controlled (25,26) and one, a non-inferiority study (26), also included an oral pramipexole treatment arm. Transdermal rotigotine treatment generally began with a five- to seven-week titration phase followed by maintenance periods of 16 (26), or 24 (25) weeks. After 16 (26) and 24 (25) weeks maintenance therapy transdermal rotigotine reduced OFF time to a significantly greater extent than placebo, and was associated with higher response rates in levodopa-treated PD patients. In a previous study, rotigotine <16 mg/24h co-administration significantly reduced the median levodopa dose required from 1400 mg/day to 400 mg/day (p=0.018), with no change in symptom control observed over a mean 11- day treatment period (UPDRS motor score) (27). In a second minor study rotigotine <24 mg/24 h reduced the UPDRS total score over a 12-week period (28,29). In the controlled phase III studies, rotigotine generated significant improvements in symptom control versus placebo (25,26). Rotigotine Morning Evening Night Morning L-Dopa Oral Agonist Figure 1 Proposed use of rotigotine for the treatment of night-time symptoms in PD patients treated with oral L-Dopa and/or dopamine agonist (between 10 pm and 8 am) Baseline PDSS 4-week Figure 2 Mean Parkinson s Disease Sleep Scale (PDSS) improvement from 88.0 (±12.2) at baseline to (±19.75) after four weeks of therapy. In the PREFER study, rotigotine 8 and 12 mg/24 h patient groups showed significant improvements versus placebo in the UPDRS ADL and UPDRS motor scores (improvements of 2.6 and 2.7 points and of 3.4 and 5.3 points, respectively) (25). Similar improvements in UPDRS ADL and motor scores in the ON condition (p<0.0001) versus placebo were observed in the CLEOPATRA-PD study with rotigotine doses of up to 16 mg/24 h. Quality of life as measured by the PDQ-39 total score was also improved (p=0.003 versus placebo) (26). The two large-scale phase III studies found that, over six months, rotigotine produced a significant reduction in daily OFF time. In the PREFER study there was a corresponding significant increase in ON time without trou- Functional Neurology 2010; 25(1):

4 A. Antonini et al. blesome dyskinesia, and no change in ON time with troublesome dyskinesia (30). The CLEOPATRA-PD study, which included oral pramipexole as an active comparator, gave similar findings (26). Responder rates (>30% reduction in OFF time) were 60, 67 and 35% for the rotigotine, pramipexole and placebo groups respectively; therefore, the first comparative data available for rotigotine for the treatment of motor fluctuations in PD indicate significant efficacy and non-inferiority to pramipexole. In addition to benefiting the ON time:off time ratio, the steady delivery of rotigotine might be expected to target the OFF problem at night, producing improvements in sleep and early morning motor function. Safety and tolerability Application site reactions are cited as the most common adverse events (AEs) in rotigotine clinical studies. About half of rotigotine patients had application site reactions (including erythema, pruritus, and dermatitis), compared with 11-21% of patients receiving placebo (15,22,26). However the majority of these events were rated as mild to moderate and dose-related (15). The safety and tolerability of rotigotine have been examined for treatment periods of up to eight months in doubleblind studies (15,22,26). Interim data for a three-year open-label extension study of rotigotine in early PD do not seem to highlight any additional concerns (31). Clinical studies in early and advanced PD found rotigotine to be generally safe and well tolerated, with most AEs being mild or moderate in severity and transient. Pooled data from placebo-controlled studies of rotigotine patients (n=1083) found that 73% of rotigotine patients reported at least one AE in comparison with 56.3% of placebo patients (30). In this pooled population the most common AEs reported by 10% of patients were nausea, dizziness and somnolence (effects consistent with dopaminergic stimulation) and application site reactions (29). In a small-scale dose-escalation study rotigotine doses of up to 24 mg/24 h were found to be well tolerated (28,29), with slow and fast titration regimens (2mg/24 h vs 4 mg/24 h increments per week) producing comparable AE profiles (29). In one study of early PD serious adverse events (SAEs) were reported in 4% of rotigotine-treated patients and 2% of placebo-treated patients (15). These SAEs included sudden onset of sleep while driving, brief loss of consciousness while driving, and unconfirmed tachycardia (15). In advanced PD, SAEs occurred at a comparable level to placebo (9 vs 9%), with SAEs in rotigotine patients including nausea, syncope, tachycardia, atrial fibrillation and application site reactions (26). For treatment periods of up to 6 months the compliance rate for rotigotine treatment was >95% in both early and advanced PD (23,25,28,29), with a high level of compliance also reported after long-term treatment in early PD (85-week, open-label extension) (29). Patient compliance With regard to compliance, studies have also reported that patients prefer the transdermal patch over oral medication; the reasons driving this preference included the once-daily administration (85%) and not having to remember to take tablets during the day (87%) (32). Overall, 95% of patients were satisfied or very satisfied with the rotigotine patch (vs 41% satisfaction with oral medication). The most common disadvantage cited was that the patch did not stay on for the entire day (56%) (32). Role of trandermal rotigotine patch in the management of Parkinson s disease In the treatment of PD there are challenges to be overcome in identifying a pharmacological agent that is both efficacious and able to be delivered in such a way as to ensure continuous dopamine stimulation. The transdermal route of administration can be considered the ideal means to achieve prolonged plasma drug concentrations and continuous dopaminergic stimulation while also being non-invasive for patients (33). Transdermal apomorphine (as a microemulsion) has also been investigated and shown potential benefits in patients with wearing off fluctuations (26,33). Rotigotine, bromocriptine, lisuride and piribedil have all been successfully transdermally delivered (27,33). Of these agents, rotigotine has undergone the most extensive evaluation as a transdermal system for the treatment of PD (32). The rotigotine transdermal patch actually offers an innovative approach for the treatment of PD and a welcome addition to drug delivery systems in this field. From the available study data it is clear that the rotigotine patch demonstrates clinical efficacy in PD, as would be expected from any D2 agonist. Its maximum recommended dose levels may require more precise definition, particularly as they differ between early (up to 8 mg/24 h) and advanced PD (up to 16 mg/24 h). With the exception of application site reactions, the tolerability of the rotigotine patch appears to be well within the range of what is known and expected from other non-ergot dopamine agonists. The potential advantages of the rotigotine patch include immediacy of effect onset as intestinal absorption is bypassed, constant drug delivery, and ease of use via application of a once-daily adhesive patch. An interesting element of this profile is constant drug delivery, which may avoid pulsatile dopaminergic stimulation, which has been postulated to be related to the development of motor complications (26). Finally, on the basis of the encouraging evidence that has recently become available it can be concluded that adding night-time rotigotine patch improves sleep problems in advanced PD patients. References 1. Curatola L, Paci C, Gobbato R et al. Parkinson s disease and parkinsonisms: imaging. Funct Neurol 2009; 24 (Suppl 1): Pacchetti C, Manni R, Zangaglia R et al. A questionnaire on sleep and mental disorders in Parkinson s disease (QS- MDPD): development and application of a new screening tool. Funct Neurol 2004;19: Pahwa R, Factor SA, Lions KE et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Qual- 24 Functional Neurology 2010; 25(1): 21-25

5 Rotigotine for the management of night-time PD problems ity Standards Subcommittee of the American Academy of Neurology. Neurology 2006;6: Silver D. Impact of functional age on the use of dopamine agonists in patients with Parkinson disease. Neurologist 2006;12: Nussbaum RL, Ellis CE. Alzheimer s disease and Parkinson s disease. N Engl J Med 2003; 348: Leopold NA, Polansky M, Hurka MR. Drug adherence in Parkinson s disease. Mov Disord 2004;19: Johnston TH, Fox SH, Brotchie JM. Advances in the delivery of treatments for Parkinson s disease. Expert Opin Drug Deliv 2005;2: Jenner P. A novel dopamine agonist for the transdermal treatment of Parkinson s disease. Neurology 2005;65(2 Suppl 1):S Löschmann PA, Chong PN, Nomoto M et al. Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N Eur J Pharmacol 1989;166: Swart PJ, De Zeeuw RA. Extensive gastrointestinal metabolic conversion limits the oral bioavailability of the dopamine D2 agonist N-0923 in freely moving rats. Pharmazie 1992;47: Pfeiffer RF. A promising new technology for Parkinson s disease. Neurology 2005;65(2 Suppl 1):S Kehr J, Hu XJ, Goiny M. Continuous delivery of rotigotine decreases extracellular dopamine suggesting continuous receptor stimulation. J Neural Transm 2007;114: Scheller D, Chan P, Li Q et al. Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson s disease. Exp Neurol 2007;203: Ravina B, Eidelberg D, Ahlskog JE et al. The role of radiotracer imaging in Parkinson s disease. Neurology 2005;64: Parkinson Study Group. A controlled trial of rotigotine monotherapy in early Parkinson s disease. Arch Neurol 2003;60: Schwarz Pharma. US prescribing information (on-line, accessed August 2, 2007) European Medicines Agency. European public assessment report (EPAR): Neupro (on-line, accessed August 2, 2007) Cawello W, Elshoff JP, Boekens H et al. Characteristics of rotigotine elimination after patch removal (abstract no. P 1164). 10 th Congress of the European Federation of Neurological Societies. Glasgow, September 2-5, Brown N, Cawello W, Horstmann R. Lack of pharmacokinetic interaction between the dopamine agonist rotigotine and levodopa/carbidopa (abstract no. 4775). 16 th International Congress of Parkinson s Disease and Related Disorders; Berlin, June 5-9, Antonini A. Nighttime rotigotine patch improves sleep in advanced Parkinson s disease patients. Poster presentation, DISMOV, Verona, Italy, March Güldenpfennig WM, Poole KH, Sommerville KW, Boroojerdi B. Safety, tolerability and efficacy of continuous transdermal dopaminergic stimulation with rotigotine patch in early-stage idiopathic Parkinson s disease. Clin Neuropharmacol 2005;28: Jankovic J, Watts RL, Martin W, Boroojerdi B. Transdermal rotigotine: double-blind placebo-controlled trial in Parkinson disease. Arch Neurol 2007;64: Watts RL, Janckovic J, Waters G, Rajput A, Boroojerdi B, Rao J. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology 2007;68: Giladi N, Boroojerdi B, Korczyn AD, Burn DJ, Clarke CE, Schapira AH; SP513 investigators. Rotigotine transdermal patch in early Parkinson s disease: a randomized double blind controlled study versus placebo and ropinirole. Mov Disord 2007;22: LeWitt PA, Lyons KE, Pahwa R; SP 650 Study Group. Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology 2007; 68: Poewe WH, Rascoll O, Quinn N et al. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson s disease: a double-blind, double-dummy, randomised controlled trial. Lancet Neurol 2007;6: Verhagen Metman L, Gillespie M, Farmer C et al. Continuous transdermal dopaminergic stimulation in advanced Parkinson s disease. Clin Neuropharmacol 2001;24: Babic T, Boothman B, Polivka J et al. Rotigotine transdermal patch enables rapid titration to effective doses in advanced stage idiopathic Parkinson disease: subanalysis of a parallel group, open-label dose escalation study. Clin Neuropharmacol 2006;29: Babic T, Boroojerdi B, Randerath O et al. Rotigotine CDS patch in advanced stage idiopathic Parkinson s disease: a parallel group open label dose escalation trial. Neurology 2004;62(Suppl 5):A Rascol O, Perez-Lloret S. Rotigotine transdermal delivery for the treatment of Parkinson s disease. Expert Opin Pharmacother 2009;10: Neurpro transdermal patch. Package label. Available on-line, last accessed 7 Jan Korczyn AD, Reichmann H, Boroojerdi B, Häck HJ. Rotigotine transdermal system for perioperative administration. J Neural Transm 2007;114: Nyholm D. Pharmacokinetic optimisation in the treatment of Parkinson s disease: an update. Clin Pharmacokinet 2006;45: Functional Neurology 2010; 25(1):