The Development of theRotigotine Transdermal PatchA Historical Perspective

Cheryl Waters, MD, FRCP(C)

KEYWORDS

� Dopamine receptor agonist � Parkinson’s disease � Rotigotine � Transdermal� Continuous delivery

KEY POINTS

� The preclinical and clinical development of the rotigotine transdermal system has estab-lished it as an effective method for providing continuous delivery of a dopamine agonistacross the skin.

� Rotigotine may have clinical advantages compared with other agents.

� Pharmacokinetic analysis of the rotigotine transdermal system has shown stable plasmalevels of rotigotine over a time period of 24 hours.

INTRODUCTION

The motor deficits associated with Parkinson’s disease (PD) result from the progres-sive loss of dopaminergic neurons in the substantia nigra pars compacta.1,2 Dopami-nergic replacement (levodopa) and dopaminergic stimulation (dopamine receptoragonists) are consequently central to the treatment of the motor deficits that typifyPD.2–4 Levodopa is the gold standard for dopaminergic therapy in PD; however, itslong-term use is complicated by the development of motor complications includingdyskinesias and the end-of-dose deterioration known as wearing off.3,5,6 These motorcomplications increase functional disability and severely affect patients’ quality oflife.7,8 Wearing-off effects are thought to indicate a shortening of the effectivenesswindow for levodopa, as a result of the progressive loss of nigrostriatal dopamine.6

Although the pathogenesis is still not fully understood, preclinical and clinical findingssuggest that the development of levodopa-induced dyskinesias is related to its shortduration of action, which results in pulsatile stimulation of striatal dopamine receptors

Disclosures: Dr C. Waters has served on the advisory board of UCB Pharma, IMPAX, and Abbot;received honoraria for speaking engagements from Teva; received institutional research sup-port from UCB Pharma, IMPAX, BIOTIE, and Abbot; and has served as a consultant for Novartis.Division of Movement Disorders, Columbia University, 710 West 168th Street, New York, NY10032, USAE-mail address: cw345@mail.cumc.columbia.edu

Neurol Clin 31 (2013) S37–S50http://dx.doi.org/10.1016/j.ncl.2013.04.012 neurologic.theclinics.com0733-8619/13/$ – see front matter � 2013 Elsevier Inc. All rights reserved.

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and altered basal ganglia output.9,10 Normal striatal dopamine receptor stimulation isthought to be continuous; therefore, continuous, rather than pulsatile, dopaminergicdrug delivery, which is based on the tonic/phasic hypothesis of dopamine release,may more closely mimic physiologic dopaminergic stimulation.10,11 This possibilityis supported by various animal studies (reviewed in detail by Jenner elsewhere inthis issue) in which continuous dopaminergic delivery has been shown to substantiallyimprove mobility and reduce the incidence of dyskinesias.12–15

The rotigotine transdermal system (Neupro) is a dopamine receptor agonist that isdelivered over a 24-hour period.16 It is approved for idiopathic PD and restless legssyndrome (RLS) in the United States and European Union.This article reviews the development of the rotigotine transdermal system for the

treatment of PD, and the clinical pharmacology of rotigotine. The results of severalphase III clinical studies have been published that support the efficacy of the rotigotinepatch for the treatment of early and advanced PD. However, this article focuses on thedevelopment of the medication from a pharmacokinetic point of view. A detailedreview discussing the results of the clinical studies can be found in the article by Lyonsand Pahwa elsewhere in this issue.

RESULTS OF PRECLINICAL STUDIES: THE PHARMACOLOGIC PROFILE OF ROTIGOTINERotigotine: the Active Compound

Rotigotine is the (–)-enantiomer of the aminotetralin derivative, 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin; (originally termed N-0437), and is structurallysimilar to dopamine.17 Early preclinical in vitro binding studies and in vivo studiesinvestigating the anti-Parkinson’s potential of N-0437 were performed on the (�) enan-tiomeric mixture of N-0437.18 However, it was found after separation of the enantio-mers that the (1) and (–) enantiomers of N-0437 showed marked differences in theirpharmacologic action; although both have been shown to act as agonists in presyn-aptic models of dopaminergic receptor activity (induction of hypomotility in mice),19

only the (–) enantiomer (–)-N-0437 was effective in postsynaptic models (rotationin 6-hydroxydopamine-lesioned rats).19 Although administration of the (–) enantiomerimproved locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates, there was no activity following administration of the (1) enan-tiomer.20,21 Preclinical studies such as these led to the development of the (–)enantiomer of N-0437 (rotigotine) for the treatment of PD [which later was also usedunder the code N-0923, whereas the (1) enantiomer was termed N-092422].

The Receptor Profile of Rotigotine

Dopamine receptor activityThe affinity and functional activities of rotigotine have been determined at a broadrange of cloned human receptors in vitro. Conventional binding assays have shownthat, of the dopamine receptors, rotigotine binds with the highest affinity to the D3receptor (inhibition constant [Ki] value of 0.71 nM), whereas its affinity is approximately20-fold weaker at the D2 receptor (Ki value 5 13.5 nM), and approximately 100-foldweaker at the D1 receptor (Ki value of 83 nM). Rotigotine also binds to the D4 (Ki of3.9 nM at D4.2, 5.9 nM at D4.7, 15 nM at D4.4) and D5 (Ki of 5.4 nM) receptors.23 Func-tional assays, measuring intrinsic activity, have confirmed that rotigotine behaves as apotent agonist at all five dopamine receptors; its potency at the D3 and D2 receptors is2600 and 53 times higher than that of dopamine, whereas it is similar to that of dopa-mine at the D1 receptor.23 Activation of the D1 receptor is unique to rotigotine amongthe non–ergot-derived dopamine receptor agonists; for example, pramipexole and

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ropinirole have been shown to act at the D2 and D3 receptors, but exhibit little or noaffinity at the D1 receptor.24,25 The ergot-derived dopamine receptor agonist, pergo-lide, does have D1 receptor properties,26 but is not widely available.The dopamine receptor–binding and activation profile of rotigotine is clearly key to

its role in PD. The role of D3, D2, and D1 receptors in the control of normal motoractivity by dopamine, and their activation in the treatment of PD, are well recognized.27

Anatomic and neurochemical studies reveal that the D3 receptor is presynapticallylocalized in the substantia nigra pars compacta and seems to play a role in modulatingdopamine release.28 The D2 receptor is abundant in the caudate-putamen of thedorsal striatum; stimulation is thought to increase locomotion.28 The D1 receptor isthe most widespread dopamine receptor in the central nervous system and is highlyexpressed in the striatum. Evidence suggests a synergistic interaction between D1and D2 receptors29–31; in the MPTP-lesioned monkey model of PD, a high-efficacyD1 receptor agonist acted synergistically with a D2 receptor agonist to prolong themotor stimulation induced by each drug alone.31

Nondopamine receptor activityAmong nondopaminergic sites, rotigotine also binds to serotonergic 5-hydroxytrypta-mine (5-HT)1A and alpha2B-adrenergic receptors, at concentrations similar to those atthe D1 and D2 receptors (Ki 5 30 nM and 27 nM).17,20,23 Rotigotine acts as an agonistat the 5-HT1A receptor, but as an antagonist at the alpha2B receptor,17,23 and this mayalso play a role in its efficacy profile.Although PD is primarily a disorder of the nigrostriatal dopaminergic pathway,

dysfunction of nondopaminergic systems, including serotoninergic and norepinephri-nergic pathways, may contribute to the development of both motor and nonmotorsymptoms.32–34 For example, depression is a common nonmotor symptom in patientswith PD and has been linked to low serotonin levels; imaging studies have reportedreduced 5-HT1A receptor binding in patients with major depressive disorderscompared with normal controls,35,36 and reductions in serotonin levels of approxi-mately 50% have been reported in the cortex and basal ganglia of patients withPD.32,34 Furthermore, alpha2-adrenoceptors located within the striatummaymodulategamma-aminobutyric acid–ergic function and contribute to the generation of dyskine-sias in PD.34 Activation of 5-HT1A receptors and inhibition of alpha2-adrenergic recep-tors have therefore been identified as potential therapeutic strategies for the treatmentof motor symptoms of PD as well as certain nonmotor symptoms, such as anxiety anddepression.34,37,38 In experimental studies, specific alpha-adrenergic receptor antag-onists, when combined with levodopa, have been shown to reduce the incidence ofdyskinesias and prolong the antiparkinsonian effect of levodopa,39 whereas thealpha2-adrenergic receptor antagonist mirtazapine, which also acts at several 5-HTreceptor subtypes, has been shown to improve depressive symptoms and sleepparameters.40 Thus, agents that target the serotoninergic and norepinephrinergicpathways, in addition to the classic dopaminergic system, may prove useful in thetreatment of PD.32

In Vivo Effects of Continuous Administration of Rotigotine

In rats, a single subcutaneous injection of the slow-release rotigotine preparationresulted in a constant level of extracellular striatal rotigotine for up to 48 hours anda concomitant sustained decrease in extracellular dopamine as measured using amicrodialysis probe inserted into the striatum.41 In 6-hydroxydopamine–lesionedrats, Schmidt and colleagues42 (2008) showed that subcutaneous administration ofslow-release rotigotine nearly abolished the induction of dyskinetic movement

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compared with pulsatile administration of rotigotine (once-daily or twice-daily intra-peritoneal injection) or pulsatile levodopa. In MPTP-lesioned marmosets, continuousrotigotine infusion (delivered via osmotic pump) reduced the expression of dyskinesiascompared with pulsatile administration (Fig. 1).43 Although both continuous and pul-satile administration of rotigotine improved motor deficits and normalized motor func-tion, animals receiving pulsatile rotigotine eventually reverted to a parkinsonian stateduring the trough of the plasma levels and were unresponsive to external stimuli duringthat period. In contrast, animals receiving continuous rotigotine performed theirnormal diurnal activities, and continued to remain responsive to external stimuli duringthat period.43

Rotigotine Toxicology

The toxicology of rotigotine has been evaluated in several preclinical studies andresults are available in summary in the prescribing information for rotigotine44 and pre-sented in detail in the marketing-authorization scientific discussion.45 To summarize,retinal degeneration has been observed in a 3-month study of rats receiving rotigotine;however, it has not been observed in routine histopathologic observation of otherspecies, and the relevance to humans is unknown. Moreover, the dose used in thisstudy was equivalent to 5.6 times the maximum human recommended dose.45 Incarcinogenicity studies in male and female rats receiving rotigotine, Leydig cell hyper-plasia and testicular and uterine tumors were observed following administration ofmedium to high doses; these tumor types are related to the well-known effect inrats on decreased prolactin levels by dopamine agonists such as rotigotine. The accu-mulated information of compounds in this class has led to the conclusion that rotigo-tine does not seem to pose a carcinogenic risk for humans.44,45 At high doses,rotigotine has been shown to reduce the motility of spermatozoa in male rats, but tohave no effect on fertility. However, fertility was reduced in female rats. The implicationof these effects for humans is not known.44,45 No clinically relevant changes in clinicallaboratory values, vital signs, physical examinations, or electrocardiogram results thatindicate toxicity have been reported in any of the human clinical studies conducted todate.1,46–50

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Fig. 1. Continuous subcutaneous application of rotigotine resulted in increased duration oflocomotor activity, increased reversal of motor disability, and shorter duration of dyskine-sias, compared with pulsatile rotigotine delivery in MPTP-lesioned marmosets. Black bars,continuous subcutaneous application of rotigotine; white bars, pulsatile rotigotine delivery.(Data from Stockwell KA, Scheller D, Rose S, et al. Continuous administration of rotigotineto MPTP-treated common marmosets enhances anti-parkinsonian activity and reducesdyskinesia induction. Exp Neurol 2009;219(2):533–42.)

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PROPERTIES OF THE ROTIGOTINE TRANSDERMAL SYSTEM

Rotigotine is highly lipid soluble, and therefore appropriate for transdermal administra-tion,16 whereas oral formulations of rotigotine undergo extensive first-pass gastroin-testinal (GI) metabolism.51,52 In a study in MPTP-lesioned marmosets, topicalapplication of an alcohol-based rotigotine solution improved locomotor activity forup to 48 hours, whereas the duration of action of the intraperitoneal and oral formula-tions was approximately 2 hours.21 Thus, these data support the administration ofrotigotine via the transdermal route. The transdermal delivery system consists of athin, silicone-based, matrix-type patch composed of 3 layers (Fig. 2) as follows:

� A flexible backing film that provides structural support and protects the drug-loaded layer from the environment

� A self-adhesive drug matrix layer that contains the active component rotigotineand inactive components

� A transparent polymer liner that protects the adhesive layer during storage and isremoved before application.44

Rotigotine drug delivery has been shown to be proportional to patch size. Hence,increasing the surface area of the patch allows the dose to be increased. For the treat-ment of PD, patches are available in several sizes: 10 cm2, 20 cm2, 30 cm2, and40 cm2; it has been estimated that the release of rotigotine from the patch is0.2 mg/cm2 over a 24-hour period. Thus, the apparent dosage of rotigotine rangesfrom 2 mg/24 h for a 10-cm2 patch containing 4.5 mg to 8 mg/24 h for a 40-cm2 patchcontaining 18 mg.44

RESULTS OF PRELIMINARY CLINICAL STUDIESProof-of-concept Studies of Rotigotine in Patients with PD

Preliminary clinical studies of early formulations of rotigotine in patients with PD sug-gested that rotigotine was efficacious for the treatment of the motor symptoms of PD.Continuous intravenous infusion of rotigotine over 4.5 hours to 9 patients with moder-ate to severe PD showed antiparkinsonian effects, as measured by a modifiedColumbia scale.53 In a 3-week, phase II, placebo-controlled, dose-finding trial of anearly patch formulation of rotigotine in 85 patients with PD, administration of the2 highest doses of rotigotine enabled the levodopa dose to be reduced (primaryoutcome).54 In a 4-week study of 7 patients with advanced PD and on/off fluctuations

Fig. 2. The transdermal rotigotine patch. (Courtesy of UCB Pharma SA, Brussels, Belgium;with permission.)

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and dyskinesias, transdermal administration of rotigotine allowed a reduction in levo-dopa dose without loss of antiparkinsonian efficacy. Moreover, there was a dose-response relationship between rotigotine dose and the reduction in levodopa, andmost patients experienced less off time and more on time without dyskinesia.55 Inthese preliminary studies, rotigotine was also well tolerated.53–55 Based on thesefavorable preliminary findings, studies to evaluate the metabolism and disposition ofrotigotine were undertaken.

Rotigotine Metabolism

The metabolism of rotigotine has been investigated in vitro in rat, monkey, and humanliver microsomes, and perfused rat livers, and in vivo in healthy humans.56–60 Thesestudies show that rotigotine is extensively metabolized in vivo, with the major routebeing conjugation of the parent compound by sulfation. A further metabolic pathway isthrough cytochrome P450 (CYP)–dependent N-dealkylation to N-despropyl-rotigotineandN-desthienylethyl-rotigotine, which are, in turn, subsequently conjugated with sul-fate or glucoronide.56,58 The main metabolites of rotigotine are thought to have littlepharmacologic activity because plasma concentrations are more than 10 times lowerthan that of the parent compound.56 Preclinical studies show that multiple CYPisoforms are able to metabolize rotigotine, suggesting that no specific CYP isoformacts as a rate-limiting factor for rotigotine metabolism.58 This is relevant when consid-ering potential drug-drug interactions, as discussed later in this article.Rotigotine metabolites are predominantly excreted by the kidneys (w71% in urine)

with w23% excreted via the feces, which corresponds with a renal clearance of12.3 L/h and fecal clearance of 4.0 L/h (Fig. 3). Less than 1% of the parent rotigotinecompound is excreted unchanged in the urine.56 Transdermal delivery of rotigotine isunaffected by food, gastric emptying or impaired gastric motility, or first-passmetabolism.61,62

Steady-state Pharmacokinetics of Rotigotine

In vitro studies conducted on excised human skin have shown linear drug permeationof rotigotine over the intended application time of 24 hours with the rotigotine patch.63

Approximately 95% of the rotigotine in a 10-cm2 patch (containing 4.5 mg rotigotine) isrecovered within 96 hours of patch application, inclusive of the residual rotigotine in

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Fig. 3. Most radiolabeled rotigotine is excreted by the kidneys. (From Cawello W, Wolff HM,Meuling WJ, et al. Transdermal administration of radiolabelled [14C]rotigotine by a patchformulation: a mass balance trial. Clin Pharm 2007;46(10):851–7; with permission.)

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the patch.57 In healthy volunteers or patients with early-stage PD, once-daily applica-tion of the rotigotine patch provided stable, dose-dependent, steady-state plasmaconcentrations over the 24-hour patch application period.64,65 Moreover, meanplasma concentrations of rotigotine were similar for different patch application sites.64

The absolute bioavailability of rotigotine after patch application is approximately 37%to 46% of the applied dose (>60% of the drug delivered to the skin).56,57 Rotigotineplasma concentrations increase over time, reaching maximum levels between 12and 24 hours after first patch application in healthy human subjects,56,57 and theydecrease quickly, with an elimination half-life of 5.3 hours, after patch removal.56 Aslight transient dip in mean rotigotine plasma concentrations has been observedover the 1 to 4 hours following the application of a new patch,66 but this is consistentwith a lag time for absorption with a new patch. Overall, plasma levels of rotigotinegenerally remain stable throughout long-term treatment.47,66 It is thought that thenegligible changes during periods of patch removal and replacement are unlikely tohave any clinically relevant impact on motor performance.

Drug-drug Interactions with Rotigotine

Drug metabolism via the CYP system is a key source of drug interactions that canresult in drug toxicity, reduced efficacy, or an increase in side effects. However, asnoted previously, multiple pathways and CYP isoforms seem to be capable of metab-olizing rotigotine; thus, if one pathway is inhibited, others can continue to metabolizethe drug.58 In vitro studies with human CYP enzymes have shown that selective inhi-bition of these CYP isoforms fails to inhibit rotigotine metabolism.58 Moreover, subcu-taneous rotigotine administration did not significantly affect CYP enzyme activity incynomolgus monkeys.58 Hence, rotigotine can be expected to have a low risk ofdrug-drug interactions. Coadministration of rotigotine with domperidone, a dopaminereceptor antagonist that undergoes extensive CYP enzymatic metabolism and that iscommonly used as an antiemetic in patients treated with levodopa or dopamine ago-nists, did not change the pharmacokinetic profile or renal elimination of rotigotine inhealthy subjects.67 These data suggest that rotigotine has a low risk of clinically rele-vant drug-drug interactions related to CYP-450 metabolism. Moreover, in patientswith RLS, the mean concentration-time profiles of rotigotine, levodopa, and carbidopawere similar during monotherapy and combination therapy, suggesting a lack ofpharmacokinetic interactions between these compounds.68 However, as would beexpected, rotigotine may potentiate the adverse effects of levodopa.44,69

Pharmacokinetics of Rotigotine in Special Populations

Because the prevalence of PD increases with age, the effects of impaired hepatic orrenal function on the pharmacokinetics of PD drugs must be considered. The pharma-cokinetics of rotigotine are similar regardless of age (<65 years and �65 years) orgender in patients with early-stage PD,64 and are similar in healthy Japanese andwhitesubjects administered a single rotigotine transdermal patch.70 Moreover, moderatehepatic impairment (Child-Pugh class B) does not seem to affect rotigotine pharmaco-kinetics or the renal clearance of unconjugated rotigotine following repeated patchapplication.71 In addition, no differences in bioavailability or total clearance of rotigo-tine were observed between healthy subjects and symptomatic volunteers with mild tosevere chronic renal insufficiency and those requiring hemodialysis72; mean plasmaconcentration-time curves of unconjugated rotigotine and the incidence of adverseevents were similar between groups.72 Taken together, these results suggest thatadjustments of rotigotine dose are not required for patients with moderate hepaticimpairment or chronic renal insufficiency.

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BENEFITS OF TRANSDERMAL DELIVERY VERSUS ORAL ADMINISTRATION

Transdermal administration may be more pharmacologically effective than oral admin-istration for patients with PD. Transdermal administration provides continuous deliveryof medication, resulting in constant plasma levels, and therefore avoids the plasmalevel peaks and troughs associated with more pulsatile oral drug delivery. Moreover,it enables controlled drug delivery over longer periods of time than with oral adminis-tration, and administration can be readily discontinued by patch removal.62,73 It mayimprove patient compliance, particularly in patients already receiving multiple oralmedications or in patients who may have difficulty swallowing.74 Transdermal deliveryalso avoids hepatic first-pass metabolism and the GI tract. GI disorders, includingdifficulty swallowing and delayed gastric emptying, are the most commonly observednonmotor symptoms of PD; the results from a retrospective claims database analysissuggest that around 65% of patients with PD have a GI disorder 4 years after diag-nosis of PD.75 Delayed gastric emptying results in increased retention in the stomach,which, in turn, leads to inconsistent intestinal absorption of orally delivered medica-tion. Thus transdermal drug delivery may be preferable to oral administration inpatients with PD with altered gastric emptying and other GI disorders.A retrospective cohort study has shown that patients with PD have significantly

longer acute hospital stays and significantly higher in-hospital mortality than individ-uals without the disease.76 Because oral PD medications often require multiple dosesthroughout the day, many patients with PD undergoing surgical procedures likely missone or more doses of medication. Thus, the management of PD symptoms in surgicalpatients is commonly problematic. Issues include postoperative confusion, worseningof PD, off symptoms, and parkinsonism-hyperpyrexia following sudden withdrawal ofdopaminergic medication.77–79 Transdermal delivery of rotigotine may be of particularvalue in patients undergoing surgery by potentially reducing the complications asso-ciated with disruption of regular medication dosing schedules.79,80 In one study, theoral PD medications (levodopa, pramipexole, ropinirole, amantadine, catechol-O-methyl transferase (COMT) inhibitors, rasagiline, and biperidine) of 14 patients withPD receiving general anesthesia79 were switched to transdermal rotigotine the eve-ning before surgery, with most patients (64.3%) able to switch from rotigotine backto prior PD medications within 24 hours following the surgery. Based on a feasibilityquestionnaire, nearly all neurologists and anesthesiologists (89% for both), and100% of patients, completely agreed (rating of 1) or agreed (rating of 2) that the trans-dermal rotigotine patch was an easily feasible option for managing perioperative PDsymptoms. Of the neurologists, 7 of 9 (78%) completely agreed (rating of 1) that nounexpected perioperative PD symptoms occurred. These findings are consistentwith those of an earlier case study80 in which no perioperative worsening of symptomswas noted for 25 patients with PD who had undergone a surgical procedure unrelatedto PD and had received rotigotine. A non–clinically important difference of 0.4 (�3.08)points was found between the preoperative and postoperative Unified Parkinson’sDisease Rating Scale (UPDRS) part III score, signifying sustained control of parkinso-nian symptoms (a difference of 2.3–2.7 points reflects a minimal clinically importantdifference on UPDRS part III81).

RESOLVING TRANSDERMAL ROTIGOTINE CRYSTALLIZATION

The formation of rotigotine crystals in the transdermal patch led to the product beingwithdrawn from the US market in 2008 because of concerns as to the impact on thebioavailability of rotigotine and the subsequent effects on efficacy. The crystallizationis caused by the formation of a more stable and less soluble polymorph of pure

Rotigotine Transdermal Patch S45

rotigotine within the patch. Because only free molecules of rotigotine can cross intothe skin, the crystals need to dissolve for rotigotine molecules to be absorbed.82 Modi-fication of the production process to inhibit the formation of crystals and implementa-tion of a cold chain storage and distribution system in which the patches arerefrigerated from the manufacturer to the patient have alleviated these concerns inEurope.82 However, in the United States, the US Food and Drug Administration(FDA) requested an alternative approach to the cold chain solution, which has led tothe development of a novel room-temperature formulation of the rotigotine trans-dermal patch. The bioavailability of this newer room-temperature formulation isconsistent with the previous formulation of the rotigotine patch, thus satisfying theFDA requirements.83

SUMMARY

The rotigotine transdermal system provides a continuous mode of delivery, and aconvenient once-a-day, nonoral option for treating the signs and symptoms of PD.It is hoped that continuous delivery provides a more physiologic option for treatingPD. Pharmacokinetic analysis of the rotigotine transdermal system has shown stableplasma levels of rotigotine within the intended application time of 24 hours, with negli-gible variation in the periods between patch removal and replacement. Rotigotine hasa low risk of drug-drug interactions because its metabolism is independent of a singleCYP-450 enzymatic pathway, and dosing adjustments are not required in patientswith hepatic or renal insufficiency. Its perioperative use in patients with PD who areundergoing surgical procedures represents a particular advantage for its transdermalmode of delivery.In conclusion, the preclinical and clinical development of the rotigotine transdermal

system has established this system as an effective method for providing continuousdelivery of a dopamine agonist across the skin, and may have clinical advantagescompared with other agents.

ACKNOWLEDGMENTS

Editorial and writing assistance for this article was provided by Richard Fay, PhD,CMPP, Evidence Scientific Solutions, Philadelphia, PA, and Emily L. Thompson,PhD, Evidence Scientific Solutions, London, United Kingdom, and was contractedby UCB Pharma, Smyrna, GA, United States.

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