Continuous dopaminergic delivery to minimize motor complications in Parkinson’s disease

Abstract

Motor fluctuations and dyskinesias are common sequelae of Parkinson’s disease (PD) that may limit function and quality of life. With disease progression, striatal dopamine concentration becomes closely linked to plasma levodopa levels, which vary considerably with standard oral regimens. Exposure of striatal dopamine receptors to wildly fluctuating transmitter levels is thought to contribute to the development of dyskinesias and motor fluctuations. Continuous dopaminergic delivery has been shown to reduce motor complications in advanced PD patients, and has been hypothesized to prevent their incidence when given as early therapy in mild PD. In this article, the authors outline the rationale for continuous dopaminergic delivery and review clinical strategies implementing the concept, including transdermal rotigotine, subcutaneous apomorphine infusion, intraduodenal infusion of levodopa gel and the investigational oral levodopa formulation IPX066.

Keywords::

• continuous dopaminergic delivery
• continuous dopamine stimulation
• Duodopa^®
• dyskinesia
• fluctuations
• IPX066
• motor complications
• Parkinson’s disease
• rotigotine

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertneurothera; (4) view/print certificate.

Release date: 31 May 2013; Expiration date: 31 May 2014

Learning objectives

Upon completion of this activity, participants will be able to:

• • Describe the rationale for use of CDD in PD

• • Describe subcutaneous and transdermal approaches to CDD in patients with PD

• • Describe use of intraduodenal infusion of levodopa gel and IPX066 as CDD options in patients with PD

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Laurie Barclay, MD

Freelance writer and reviewer, Medscape, LLC

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Brenton A Wright

Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY, USA

Disclosure: Brenton A Wright has disclosed the following relevant financial relationships: Receives fellowship support from the Parkinson’s Disease Foundation.

Cheryl H Waters

Albert B and Judith L Glickman Professor of Clinical Neurology; Division of Movement Disorders, Columbia University College of Physicians & Surgeons, New York, NY, USA

Disclosure: Cheryl H Waters has disclosed the following relevant financial relationships: Receives honoraria for speaking from UCB.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc) leading to bradykinesia, rigidity and tremor in addition to a variety of well-characterized nonmotor symptoms. The standard treatment of motor symptoms in PD is dopaminergic replacement therapy with either the dopamine precursor levodopa or dopamine agonists, with levodopa remaining the most efficacious therapy to date. With disease progression, the duration of symptomatic relief with each dose may become progressively shorter, wearing off may become sudden and unpredictable, and periods of relief may become complicated by abnormal dyskinetic movements [1]. Motor complications occur in up to 50% of patients taking levodopa for >5 years and in as many as 100% of patients with young-onset PD [2,3], and are a major cause of disability. Although deep brain stimulation (DBS) has been shown to be effective for motor fluctuations it carries risks, is expensive, and is contraindicated in patients with cognitive dysfunction and significant psychiatric comorbidities. It would be advantageous to develop medical treatment strategies that are able to treat Parkinsonism as effectively as oral levodopa while minimizing motor complications. In this article, the authors review treatment strategies designed to achieve this goal. First, the concept of continuous dopaminergic stimulation (CDS) and its evolution towards continuous dopaminergic delivery (CDD) are discussed, and then the approaches are assessed individually.

CDS & the transition to CDD

The concept of CDS has been influential in recent years and has led to increased prevalence of dopamine agonist monotherapy for early PD [4–6]. Under normal physiologic conditions in the striatum, SNc neurons fire tonically at a rate of 3–6 Hz, with superimposed phasic firing activity occurring in response to stimuli [7–9]. Despite intermittent phasic activity, the dopamine concentration in the striatum is maintained at constant levels [10] due to presynaptic storage of dopamine, which buffer the varying amounts of transmitter in the synapse. The constant concentration of striatal dopamine, and therefore, continuous stimulation of postsynaptic receptors, is thought to be essential for normal basal ganglia function [11]. With loss of SNc dopamine neurons in PD, presynaptic stores become depleted, and with disease progression striatal dopamine concentration becomes closely linked to the concentration of levodopa in the plasma, which varies according to the oral levodopa dosing schedule. This nonphysiologic pulsatile stimulation of dopamine receptors is thought to induce molecular changes in striatal neurons and neurophysiologic changes in their outputs, which manifest clinically as motor fluctuations and dyskinesias [12]. It should be noted that while details underlying motor fluctuations and dyskinesias are poorly understood, independent mechanisms at the molecular, synaptic and circuit level are thought to underlie the two phenomena – the details of which will not be discussed in this article.

The plasma half-life of levodopa in the carbidopa–levodopa immediate-release formulation is approximately 90 min [13], while all oral dopamine agonists have half-lives greater than 6 h [11]. Laboratory studies in MPTP-lesioned primate models of PD have consistently shown that development of dyskinesia phenotypes is closely linked to intermittent levodopa administration (relative to dopamine agonists); and that once present, such dyskinesias are significantly reduced by switching from levodopa to dopamine agonists [14–18]. The ELLDOPA trial demonstrated that motor complications in early PD patients treated with levodopa are dose-related, and occur earlier than had been previously thought [19]. It is well-established that in early PD, there is significantly decreased incidence of dyskinesia with dopamine agonist monotherapy when compared with levodopa [20–23]. For example, oral ropinirole with as-needed levodopa supplementation compared with levodopa therapy alone has been shown to delay the incidence of dyskinesia by up to 10 years [22,24]. The concept of CDS sought to explain these findings based on the plasma half-life, and therefore the putative duration of action of these drugs. By extension it was proposed that the onset of dyskinesias and motor fluctuations could be delayed or prevented by achieving continuous stimulation of striatal dopamine receptors using long-acting medicines such as dopamine agonists.

The CDS theory has fallen out of favor for a variety of reasons. Incidence of dyskinesias has not been proven to be directly correlated with drug half-life. In a primate model of PD, while dopamine agonists did induce less dyskinesia than levodopa, the effect appeared to be no different between long-acting and short-acting agonists [16]. Comparisons across clinical studies suggest that risk of dyskinesia may be greater for cabergoline (t_1/2: 72–96 h) than pramipexole (t_1/2: 6 h) [25]. In addition, despite their long plasma half-lives, oral dopamine agonists do not achieve CDS, as most require thrice-daily dosing to be clinically effective. A recent meta-analysis of dopamine agonist trials for PD showed that the mean daily reduction in ‘off’ time (2.1 h; 95% CI: 1.6–2.8) occurred irrespective of the variability in drug half-life (range: 1–100 h) [26].

Oral dopamine agonist binding is highly specific for D2/D3 receptors with very little effect on other receptor subtypes [27]. Levodopa, once converted to dopamine, has activity at all five dopamine receptor subtypes and also has effects on glutamatergic, serotonergic and noradrenergic transmission [28]. This invokes alternative mechanisms, other than solely the plasma half-life on which CDS relies, to explain increased incidence of motor complications with levodopa relative to agonists. Experiments with MPTP-lesioned primates showed that subjects receiving continuous subcutaneous delivery of apomorphine remained in the ‘on’ state for the duration of the study with minimal dyskinetic movements, while subjects given intermittent apomorphine injections developed both peak dose dyskinesias and wearing off effect [29]. Thus, changing the delivery profile of an identical drug, even one with a half-life shorter than levodopa, seems to be able to lower the risk of motor complications. In recent years, CDS has largely been displaced by the concept of CDD. CDD aims to minimize motor fluctuations in PD by delivering the drug in as constant a manner as possible, regardless of serum half-life. CDD can be thought of as a practical modification of CDS that does not rely upon poorly understood conceptions of events occurring at the level of the dopamine receptor and striatal output circuitry [28]. In subsequent sections, the authors outline and assess several approaches to achieve CDD of varying novelty and efficacy.

Controlled-release levodopa & catechol-O-methyltransferase inhibitors

The controlled-release (CR) formulation of carbidopa–levodopa, with plasma half-life of approximately 1.7 h [30] was thought to have the theoretical potential for less pulsatile dopaminergic stimulation, and was compared with the standard immediate-release formulation (t_1/2: 90 min) in several randomized blinded trials. These studies demonstrated no difference in the incidence in dykinesias and motor fluctuations with the CR formulation [31–34]. The intestinal absorption of carbidopa–levodopa-CR is incomplete and variable. Not only is the formulation poorly suited for continuous drug delivery, but also for providing relief of motor symptoms in a timely fashion.

Entacapone inhibits the catechol-O-methyltransferase enzyme, which blocks peripheral metabolism of levodopa and extends its plasma half-life [35]. STRIDE-PD was a prospective, double-blind trial comparing IR carbidopa–levodopa with a combined carbidopa–levodopa–entacapone formulation (brand name Stalevo^®, Novartis, UK) in early PD. Unfortunately, the patient arm receiving entacapone had a shorter time to onset of dyskinesia (hazard ratio: 1.29; p = 0.04) as well as increased frequency of dyskinesia at the end of the study (42 vs 32%; p = 0.02) when compared with the standard carbidopa–levodopa group [36]. It should be noted that in trials evaluating both approaches, patients in the experimental arm (carbidopa–levodopa-CR or carbidopa–levodopa–entacapone, respectively) received slightly higher bioequivalent levodopa doses than the groups receiving standard carbidopa–levodopa. However, in both cases, reduction in total daily ‘off’ time and difference in UPDRS was not clinically significant. Thus, neither the carbidopa–levodopa CR formulation nor the addition of entacapone has been shown to be effective in reducing motor complications. Neither approach is able to achieve the pharmacokinetics/pharmacodynamics of CDD; in retrospect, these data may not be surprising.

Intravenous levodopa & subcutaneous apomorphine infusion

For many years it has been known that continuous intravenous infusion of levodopa can effectively treat symptoms of advanced PD while minimizing motor complications in the short term, even in patients already suffering from severe fluctuations [37–39]. Indeed, these observations prompted the pursuit of the CDD strategy. However, as levodopa is rapidly oxidized in aqueous solution, it requires an acidic solution to maintain stability, therefore administering the drug safely requires large fluid volumes. Even diluted as such, the infusion irritates the veins and soft tissues, and cannot be maintained longer than 7–10 days [40].

Apomorphine, which has activity at striatal D1/D2 receptors, is the most potent dopamine agonist and can provide anti-Parkinson’s effect comparable to levodopa [41,42]. When injected subcutaneously it is rapidly absorbed, with effect noticeable in 5–15 min. In PD patients with motor fluctuations, intermittent subcutaneous injections can be given to treat acute ‘off’ states, although the effect is short-lived [43]. Small clinical studies of continuous apomorphine delivery, utilizing subcutaneous pumps similar to insulin pumps, have suggested this to be a viable option in PD patients with motor complications. In their review of these studies, Antonini and Odin reported that overall there was a reduction in ‘off’ time (range: 50–80%) that was consistent across studies. Some studies reported improvement of dyskinesias while others did not [42]. It should be noted that all such studies were small, nonrandomized and nonblinded.

Subcutaneous apomorphine infusion has a high risk of inducing severe nausea, and it is therefore recommended that patients are pretreated with the oral antiemetic domperidone (a drug that is not currently approved for prescription in the USA) three to four times daily. When given as monotherapy, high doses of apomorphine (>100 mg/day) are required to adequately treat Parkinsonian symptoms; in general, patients are not able to tolerate doses this high [40]. Thus most patients need to supplement the infusion with oral levodopa, which reintroduces the nonphysiologic pulsatile stimulation of dopamine receptors that the strategy was designed to eliminate. Common adverse events observed included subcutaneous nodules (70%), somnolence (23%), nausea/vomiting (10%), renal impairment (6%), positive Coomb’s test (6%) and orthostasis. In addition, patients receiving long standing apomorphine (up to 16 h/day for 2 years) are at risk for impulse control disorders and other psychiatric side effects [40], which can lead to serious life-altering events and require discontinuation of the drug. At present, it appears that, although both continuous intravenous levodopa and subcutaneous apomorphine have the potential to reduce motor complications in the short term, their significant adverse effects prohibit them from widespread clinical practice.

Prolonged-release formulations of dopamine agonists

In recent years, extended-release (ER) formulations of pramipexole and ropinirole have become available. These ER formulations have been shown to have comparable efficacy with their immediate release counterparts both in early and advanced PD [44–46]. They are administered once daily, as opposed to three-times daily with standard dopamine agonists. Pharmacokinetic data with both pramipexole and ropinrole have shown that the ER formulations of both drugs are able to provide a more constant, smooth plasma concentration profile than regimens of their immediate release counterparts [47,48]. Although therapeutic efficacy appears to be similar for both regimens, once-daily administration of ER formulations has the potential to improve medication compliance and therefore clinical outcomes [49–51]. Whether there is a difference in dyskinesia incidence when immediate-release and ER dopamine agonist formulations are compared as early monotherapy has yet to be studied.

Watts et al. carried out a randomized blinded trial in patients already on levodopa (≤600 mg/day) whose motor symptoms were not adequately controlled. In such patients, the addition of prolonged-release ropinirole was compared with the addition of higher levodopa dosage, with onset of dyskinesia as the primary end point [52]. The incidence of dyskinesia was 3% in the prolonged-release ropinirole group, and 17% in the group receiving additional levodopa, with comparable treatment efficacy in both groups. No impulse control disorders or unexpected sleep episodes were reported in the trial. However, it should be noted that because the sponsor terminated the study early (due to low enrollment and low early estimates of dyskinesia incidence later found to be incorrect), a smaller sample size and shorter observation period than originally intended was utilized [52]. In addition, there was no comparison with the immediate-release formulation of ropinirole, so it is unclear if the prolonged release form is superior at reducing onset of dyskinesia than standard ropinirole.

Continuous transdermal delivery of rotigotine

Rotigotine is a non-ergot dopamine agonist formulated in a silicone-based transdermal patch. The transdermal delivery system maintains a stable drug release profile allowing for a steady-state plasma concentration of rotigotine while the patch is in place [53]. Placebo-controlled trials showed rotigotine to be an effective treatment for early PD [54,55]. Given the capacity for continuous drug delivery, it has been evaluated for management of motor complications. The PREFER study was a double-blind, prospective trial for patients with advanced PD and >2.5 h of daily ‘off’ time despite oral levodopa therapy. Patients were randomized to placebo patch versus 8 or 12 mg transdermal rotigotine. Daily mean ‘off’ time was reduced 1.8 h for the 8-mg patch and 1.2 h for the 12-mg patch [56]. Both doses increased ‘on’ time without dyskinesia, although again there was a more robust effect with the 8-mg dose (+2.4 h) than with that of the 12-mg dose (+1.1 h). In another trial using similarly selected advanced PD patients, transdermal rotigotine and oral pramipexole arms were studied against placebo. Rotigotine was shown to be noninferior to pramipexole for reduction in daily ‘off’ time [57]. Both agents increased ‘on’ time without dyskinesia without increasing ‘on’ time with dyskinesia. However, responder rates (proportion of patients with ≥30% reduction in daily ‘off’ time) were somewhat higher for the pramipexole group [57]. Similarly, in a study comparing rotigotine to ropinirole in early PD, rotigotine was shown to have a less robust symptomatic effect [58], although one cannot be certain of dose equivalency.

Adverse reactions in the aforementioned studies were mild, the most common being local skin reactions at patch sites. In an open-label extension of one of the early-PD rotigotine trials [54,59], 47% of 217 patients remained on rotigotine at the end of the study (median exposure time: 5.25 years). 24% of patients withdrew from the study due to adverse events and 6% due to lack of efficacy (24% for other reasons). Common adverse events included somnolence (23.4% per patient year), falls (16.5%), peripheral edema (14.2%), nausea (12.4%), application site reactions (11.7%), hallucinations (10%) and compulsive behaviors (8%) [59]. Only 25% of patients in the study developed dyskinesias, and 83% of these were reported in patients who had their first episode after starting adjunctive levodopa. The 25% dyskinesia incidence rate was similar to that observed in past trials of oral dopamine agonists, which also permitted concomitant levodopa [20–24]. It should be noted that during the study period, 74% of patients did start levodopa and 6% stopped rotigotine due to lack of efficacy. The rotigotine patch is able to provide continuous drug delivery, but appears to only be practical as monotherapy for a few years until stronger symptomatic medicines are required.

Continuous duodenal levodopa infusion

Although intravenous infusion of levodopa provided proof-of-concept that CDD can ameliorate motor complications in advanced PD patients, this approach is not clinically feasible as previously discussed [40]. One of the reasons that it has been difficult to achieve constant plasma concentrations of levodopa with orally administered formulations is that absorption of the drug in the proximal small intestine is dependent on gastric emptying, which is highly variable. This problem can be circumvented using a stable concentrated gel (levodopa–carbidopa 20/5 mg/ml in a caboxymethylcellulose mix, aka Duodopa^®) delivered directly into the duodenum via a percutaneous endogastric gastrostomy and portable infusion pump [60]. With a constant infusion rate of the levodopa–carbidopa gel during the waking hours, smooth plasma levodopa levels, and therefore, more continuous stimulation of striatal dopamine receptors can be achieved. This has been shown to be a successful strategy to minimize motor fluctuations and dyskinesias in advanced PD patients, in addition to providing a more consistent clinical benefit [42,61] and enhanced quality of life (QoL) [62,63].

A randomized, controlled multicenter trial (DIREQT) showed continuous intraduodenal infusion of levodopa gel to be safe, effective and advantageous in patients with preexisting dyskinesias and motor fluctuations [64]. Twenty four patients were studied in a crossover design, which compared continuous enteral infusion with optimized individual oral regimens for two periods of 3 weeks. Patients were assessed based on blinded video evaluations as well as motor function and QoL self-assessments. The primary end point was the percentage of ratings spent within a scoring range that corresponded to a functional ‘on’ state (mild Parkinsonism without dyskinesia and ‘on’ with mild dyskinesia were included as the lower and upper range values, respectively). While on optimized oral regimens, patients fell within the functional ‘on’ range for 81.3% of the ratings; and during levodopa gel infusion, the same patients fell within the range for 100% of the ratings [64]. The improvement was accompanied by a decrease in ‘off’ state without increase in dyskinesia.

The most common adverse events are related to mechanical problems with the intestinal tubing (kinking, dislocation from the pump) and complications of the gastrostomy (infection, secretion from the stoma, localized pain) [40]. If the tubing becomes obstructed, there may be acute worsening of Parkinsonism. This also may occur if the distal end of the tube is displaced to the stomach, or there may be re-emergence of motor complications with variability in gastric emptying. In another open-label prospective trial, nine advanced PD patients receiving intraduodenal infusion were followed for 12 months [65]. Two of the nine patients withdrew from therapy. One patient withdrew after she developed marked confusion and visual hallucinations 1 month after starting the enteral infusion. These symptoms improved after the patient was switched back to an oral regimen with the addition of an atypical neuroleptic. The other developed acute peripheral neuropathy after 7 months; given this time course, the authors expressed doubt that this was directly related to the duodenal infusion.

Although the enteral infusion appears to provide CDD, it is an exogenous, and therefore nonphysiologic process. This raises concern that tolerance may develop to levodopa over time, as well as toxicity (psychosis, hallucinations). The DIREQT trial excluded patients with dementia and psychiatric complications [64]. A recent retrospective study evaluated characteristics of all patients in France (n = 91) receiving duodenal levodopa infusion from 2003 to 2008 [66]. All had advanced PD with motor complications. In 98% of cases, duodenal infusion was the last line of treatment due to cognitive/psychiatric comorbidities that prohibited DBS or subcutaneous apomorphine pump. Before initiation, 42% of patients had severe, persistent visual hallucinations. None of these patients reported worsening of hallucinations during the study, although antipsychotics (90% clozapine) were utilized [66]. 92% reported improved QoL. In this series, the most common adverse events included technical problems (pump/tubing complications), which occurred in 62.6% (n = 57) of patients.

Interim results of the largest open-label trial of intraintestinal levodopa infusion carried out internationally have recently been reported [67]. In 192 advanced PD patients who were prospectively studied, daily ‘off’ time was reduced by a mean of 3.9 h (±3.2) and ‘on’ time without troublesome dyskinesia was increased by 4.6 h (±3.5). Mean duration of therapy was 256.7 days (±126). Adverse events were similar to those observed in the French retrospective study, with perioperative events, abdominal pain and mechanical complications being the most common. Of note, no patients have developed visual hallucinations or psychosis to date. However, four patients did develop new-onset polyneuropathy; in one patient this was severe enough to discontinue levodopa infusion. One patient improved with vitamin B12/B6 supplementation. As previously mentioned, in a smaller earlier trial, one of the nine patients developed neuropathy after starting the infusion [65].

The significance and possible causality of incident neuropathy remains unclear. Several studies have linked increased incidence of neuropathy in PD patients with cumulative levodopa dose and elevated serum methylmalonic acid levels [47,48]. It has been proposed that levodopa may disrupt the metabolic pathway of colabamin (B12), leading to elevation of serum methylmalonic acid and homocysteine, as well as B12 deficiency [29]. Another hypothesis is that continuous intestinal infusion interferes with absorption of vitamins necessary for normal homocysteine metabolism. Some authors have recommended that patients using intraintestinal levodopa infusion (as well others taking high doses of oral levodopa) be given B12/B6 supplementation and have the appropriate serum labs monitored regularly [29]. Further studies are required to obtain a better understanding of this rare adverse event, and more information will be gathered as clinical experience with the infusion system accumulates.

Because of putative risk of dopamine toxicity (psychosis), 24-h infusion has not been recommended and in practice most patients deactivate the pump overnight. With overnight withdrawal from levodopa, patients would be expected to be in an ‘off’ state in the morning and may require assistance in connecting and activating the pump. In the French retrospective study, a caregiver was required for morning set-up in 94% of cases [66].

As this treatment strategy involves a minor surgical procedure and prosthetic device, it has only been used in advanced PD patients. Because of obvious practical considerations, it has not yet been studied whether continuous enteral levodopa delivery initiated early in the course of PD may prevent the incidence of motor complications, although in theory this seems plausible and testable.

Novel ER formulation of oral carbidopa–levodopa: IPX066

As previously discussed, the CR formulation of levodopa is variably absorbed, the time to effect is delayed and the duration of clinical benefit is only mildly extended [30–32]. Recently, the investigational drug IPX066 has emerged as a novel ER formulation. This tablet is composed of carbidopa–levodopa-filled microbeads designed to dissolve at various rates in the small bowel, allowing for absorption over a longer period of time. IPX066 is designed to provide rapid absorption and clinical effect, as well as to sustain therapeutic serum levodopa levels for longer periods [68]. In an open-label crossover study, 27 advanced PD patients were randomized to 8-day treatment with immediate release carbidopa–levodopa (CD-LD IR) followed by 8 days with IPX066, or IPX066 followed by CD-LD IR [69]. For the IPX066 periods, initial q6h dosing was suggested, and during the first 3 days of each period the dosing regimen could be adjusted to optimize symptom relief.

On the first day of treatment, single-dose pharmacokinetics were assessed via plasma levodopa measurements. Initial absorption rates were similar for both drugs: time to reach 50% of C_max was 0.76 h for CD-LD IR and 0.78 h for IPX066 [69]. Plasma levodopa concentrations were more sustained with the study drug, remaining above 50% of C_max for 4 h with IPX066 and only 1.4 h with CD-LD IR (p < 0.0001). On day 8 of each treatment period, multiple-dose pharmacokinetics were evaluated. The plasma levodopa concentration fluctuation index was more than 50% lower with IPX066 than CD-LD IR (1.5 vs 3.2; p < 0.0001) and mean levodopa C_max/C_min ratio was more than sevenfold lower with IPX066 (12 vs 82.2; p < 0.0001) [69].

Clinical assessment indicated that UPDRS motor scores and the percentage of patients in the ‘on’ state without troublesome dyskinesia were significantly more favorable with IPX066 when evaluated 3–6 h after a single dose. In addition, patient diaries suggested that ‘off’ time was reduced 2.11 h per day during the IPX066 periods, relative to 0.11 h with CD-LD IR (p < 0.0001), although there was no significant difference in ‘on’ time with troublesome dyskinesia. These data are preliminary given the small study size, open-label design and short treatment period. However, in a recently published Phase III study of 393 patients over a 13-week period using a randomized blinded double-dummy design, IPX066 (mean: 3.6 daily doses) reduced ‘off’ time by an average of 1.17 h (95% CI: 0.66–1.69) more than CD-LD IR (5.1 daily doses) [70]. Adverse events were minor and similar between the two groups. The authors reported that one patient in the CD-LD IR group and three patients in the IPX066 group developed impulse control disorders; given the low overall frequency of this side effect in the study it is unclear if the IPX066 regimen consistently introduces a higher risk.

It should be noted that in the aforementioned studies, optimized treatment required much higher mean daily levodopa doses during the IPX066 periods (2054.4 mg divided into 3.5 daily doses) than the CD-LD IR periods (787.3–816.7 mg; 5.4 daily doses) [69]. Even considering that levodopa from IPX066 is only 74.5% bioavailable, this dose discrepancy has raised some concern given what is known about cumulative levodopa dose and the development of motor complications [71]. However, the high doses of levodopa linked to incidence of motor fluctuations and dyskinesias in past studies were delivered in pulsatile form [19,20]. With more continuous levodopa delivery, a plasma concentration curve with peaks and valleys is replaced by a more level curve. By eliminating the peaks but filling in the valleys, maintaining a steady-state plasma concentration requires a higher total daily levodopa dose but this higher dose is not conceptually the same as an equivalent amount given in a pulsatile manner. Therefore, although the IPX066 formulation may require more total levodopa to be taken in orally, this does not theoretically translate to a higher risk of dyskinesia and motor fluctuations, and indeed the smoother level is hoped to prevent their incidence. Currently, IPX066 remains an investigational compound; the review process for the US FDA approval is in progress.

Expert commentary

Motor complications are a common sequelae of PD that can dramatically affect function and QoL. Laboratory and clinical studies show that although both motor fluctuations and dyskinesias are closely linked to the short serum half-life of levodopa, other factors may also play a part. Evidence in early PD clearly shows a decreased incidence of motor complications with dopamine agonist monotherapy relative to levodopa [20–23]. However, dopamine agonists may cause serious side effects such as impulse control disorders and sleep attacks, and they are less effective at treating Parkinsonism. Long-term studies show that most patients on agonists will eventually require levodopa and that subsequently these individuals will develop dyskinesias and fluctuations at rates comparable to those who started levodopa early [72]. DBS has been shown to reduce levodopa-associated motor complications, but this is expensive and may be contraindicated in patients with cognitive, psychiatric or medical comorbidities. In such patients, CDD may be a viable alternative.

In patients with advanced PD, continuous intraintestinal infusion of levodopa gel is a well tolerated and effective approach to minimizing fluctuations and dyskinesias, as evidenced by years of clinical experience in Europe. This system has received the fast track designation by the FDA, and is expected to be approved for clinical implementation in the USA soon. Patients should be aware that mechanical issues with the infusion system are not uncommon, and that living in a location that allows for timely access to a gastroenterologist or surgeon who can fix such problems is important. They should also be aware that a caregiver will almost certainly be required to connect and activate the pump in the morning. Polyneuropathy has been observed as a rare adverse event and may be related to abnormal vitamin B12/B6 metabolism; further study is needed to understand the nature of the association with the enteral infusion system.

Subcutaneous apomorphine infusion, only available in Europe, can also help with late stage motor fluctuations. However, doses of apomorphine required to treat advanced Parkinsonism as monotherapy are poorly-tolerated, and patients should be aware that supplementation with oral levodopa will likely be necessary. Subcutaneous nodules are common, as is nausea. Nausea as an early side effect can be counteracted with thrice-daily domperidone, which can often be withdrawn after several weeks as patients acclimate to the delivery system. In addition, there is a consequential risk of impulse control disorders and psychosis. Unlike continuous duodenal infusion, with which hallucinations can usually be controlled with atypical antipsychotics, the apomorphine pump is contraindicated in patients with psychosis and/or severe dementia.

Unfortunately, the STRIDE-PD study showed that initial therapy with carbidopa–levodopa–entacapone in early PD decreased time to onset of dyskinesia, and led to an increased frequency of dyskinesia in the study arm relative to standard carbidopa–levodopa [36]. Although prolonged-release formulations of dopamine agonists taken once daily are able to achieve more stable plasma concentration profiles than immediate release thrice-daily regimens [47,48], clinical efficacy and reduction in ‘off’ times appears to be comparable [44–46]. Currently, prolonged-release dopamine agonists are mainly advantageous in that they can improve patient compliance. Whether early monotherapy with prolonged-release agonists can reduce the development of dyskinesias and/or motor fluctuations has yet to be studied.

The rotigotine transdermal patch does achieve CDD with steady-state plasma concentration [53], and can be effective in reducing ‘off’ time when added to a levodopa regimen. The side-effect profile is expected to be similar to that of oral dopamine agonists (including impulse control disorders, somnolence, weight gain and peripheral edema) with the exception of local skin irritation reactions, which are unique to the patch. No studies have addressed whether the patch delays the onset of motor complications when given as monotherapy for early PD, either compared with levodopa or oral agonists. Rotigotine was temporarily recalled from the US market due to occasional crystallization of the compound within the patch and consequent decreased transdermal absorption. This delivery system problem has been fixed; and in 2012 rotigotine re-entered the US market as the Neupro^® patch (UCB, Inc., GA, USA).

A patch providing continuous delivery of levodopa would be ideal. However, soluble levodopa requires a solution with high acidity. A study utilizing a transdermal delivery system with levodopa ethyl ester was able to achieve stable plasma levodopa concentrations, but the patch was limited by problems with severe local skin reactions [73,101]. Although this endeavor was terminated for this reason, there are plans to develop a transdermal system utilizing a levodopa prodrug that may be less irritating to the skin [101].

IPX066 is a promising form of oral levodopa that rapidly delivers and sustains long-lasting therapeutic plasma concentrations relative to standard IR and CR tablets. This is theoretically attractive in that it utilizes the most clinically effective medicine, minimizes the nonphysiologic pulsatile stimulation of striatal dopamine receptors and avoids invasive procedures or prosthetic equipment. As an oral medication, it has more practical potential for assessment as a treatment for early PD than the more invasive approaches. However, current data in advanced PD are preliminary, and it will be years before any conclusions from studies done with early PD patients can be drawn.

Five-year view

Since its re-entry into the US market, the rotigotine patch has been widely used to smooth out motor fluctuations in PD patients, often as an adjunct to oral levodopa. This will continue and more patients with be offered this option as providers gain experience. Continuous duodenal infusion of levodopa gel is expected to gain approval for clinical practice in the USA, and will be available to advanced PD patients as an alternative to DBS. IPX066 is also likely to be approved by the FDA. It should be available to PD patients at all stages, although cost will be higher than older medications. Later-stage fluctuating PD patients taking carbidopa–levodopa IR in dosing intervals of 3 h or less will be able to switch to IPX066 given three- to four-times daily. This will smooth out clinical response and provide a more convenient regimen. It has been predicted that once IPX066 enters the market there will be a study to see if its utilization as an initial treatment in early PD can prevent the incidence of dyskinesia [68].

A limitation the orally-administered levodopa is that gastrointestinal absorption only occurs in a relatively short segment of the proximal small intestine. Preliminary investigations are underway for the experimental compound XP212179. This is a levodopa prodrug that is taken up by high-capacity nutritional transporters that are present throughout both the small and large bowel [73]. Once absorbed, XP212179 is converted to levodopa in the bloodstream by nonspecific enzymatic pathways. A more extensive absorption area allows for a much longer absorption period, giving this oral compound potential to provide levodopa delivery in an even more continuous manner. A small Phase I study found that XP212179 to be safe, able to provide more sustained plasma levodopa concentrations, and able to reduce ‘off’ time >30% in the majority of tested patients relative to carbidopa–levodopa IR [74]. Although more extensive studies are needed, it is not inconceivable that this compound or other levodopa prodrugs will be available for clinical practice within the next 5 years.

Motor fluctuations and dyskinesias are common in PD and remain a significant impediment to patient function and QoL. CDD strategies are allowing us to make progress with their management. New approaches on the cusp of the market and within the research pipeline will help us to do an even better job, and may even have the potential to prevent their incidence at the outset.

Key issues

• • Motor complications are a major consequence of Parkinson’s disease (PD) progression and treatment, and have been strongly linked to oral levodopa.

• • Nonphysiologic, pulsatile stimulation of striatal dopamine receptors is thought to significantly contribute to motor fluctuations and dyskinesias.

• • Although studies show that motor complications are closely linked to the short-serum half-life of levodopa, other factors may also play a role.

• • Dopamine agonists are associated with adverse effects such as impulse control disorders and sudden somnolence. With time, PD patients on agonists will require levodopa and will subsequently face the same risk of motor complications.

• • The concept of continuous dopaminergic delivery has come into favor in place of continuous dopaminergic stimulation for management and prevention of motor complications.

• • The STRIDE-PD study showed that early treatment with carbidopa–levodopa–entacapone increased incidence and frequency of dyskinesia.

• • Subcutaneous apomorphine infusion can provide continuous dopaminergic delivery, though there is risk of psychosis, and supplementation with oral levodopa may be required.

• • Transdermal rotigotine achieves steady-state plasma drug levels and can be effective to increase ‘on’ time. Local skin reactions are the most common side effects, though similar adverse events to oral dopamine agonists are possible.

• • Continuous intraduodenal infusion of levodopa gel is well tolerated and effective in minimizing motor fluctuations in patients with advanced PD. Mechanical problems with the pump and tubing system are the most common adverse events. Rare incidence of polyneuropathy has been reported and could be related to changes in vitamin B12 metabolism and/or absorption.

• • IPX066 has both rapid and delayed absorption of carbidopa–levodopa to provide a more constant serum levodopa concentration, achieving both immediate and sustained clinical effect. Preliminary data show that it can reduce motor fluctuations and dyskinesias in advanced PD patients.

• • IPX066 given as initial therapy in early PD may have the potential to reduce subsequent incidence of motor complications. This has yet to be studied.

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Continuous dopaminergic delivery to minimize motor complications in Parkinson’s disease

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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2. The material was organized clearly for learning to occur.
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1. Based on the review by Drs Wright and Waters, which of the following statements about the rationale for use of continuous dopaminergic delivery (CDD) in Parkinson’s disease (PD) is most likely correct?

• □ A Standard oral regimens of levodopa result in consistent dopamine levels due to the long half-life of levodopa

• □ B Physiologic, ongoing stimulation of striatal dopamine receptors is the main cause of motor fluctuations and dyskinesias in PD

• □ C Adverse effects of dopamine agonists include impulse control disorders and sudden somnolence

• □ D In the STRIDE-PD trial, early treatment with carbidopa–levodopa–entacapone reduced dyskinesias

2. Your patient is a 63-year-old male with mild, early PD. Based on the review by Drs Wright and Waters, which of the following statements about subcutaneous and transdermal approaches to CDD ismost likely correct?

• □ A Subcutaneous apomorphine does not have significant adverse effects

• □ B Subcutaneous apomorphine does not generally require adjunctive therapy

• □ C Rotigotine is a non-ergot dopamine agonist in a silicone-based transdermal patch that achieves steady-state plasma drug levels and effectively increases ‘on’ time

• □ D Adverse reactions of rotigotine are severe and generally preclude its use

3. Based on the review by Drs Wright and Waters, which of the following statements about use of intraduodenal infusion of levodopa gel and IPX066 as CDD options in patients with PD would most likely be correct?

• □ A Continuous intraduodenal infusion of levodopa gel is poorly tolerated and not very effective in minimizing motor fluctuations in patients with advanced PD

• □ B Polyneuropathy is a common complication of continuous intraduodenal infusion of levodopa gel

• □ C Many randomized controlled trials have proven that IPX066 given as initial therapy in early PD reduces subsequent incidence of motor complications

• □ D The effect of IPX066 is both immediate and sustained due to both rapid and delayed absorption of carbidopa–levodopa