Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20

Apomorphine hydrochloride for the treatment of Parkinson’s disease Elisa Unti, Roberto Ceravolo & Ubaldo Bonuccelli To cite this article: Elisa Unti, Roberto Ceravolo & Ubaldo Bonuccelli (2015) Apomorphine hydrochloride for the treatment of Parkinson’s disease, Expert Review of Neurotherapeutics, 15:7, 723-732, DOI: 10.1586/14737175.2015.1051468 To link to this article: http://dx.doi.org/10.1586/14737175.2015.1051468

Published online: 02 Jun 2015.

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Drug Profile

Apomorphine hydrochloride for the treatment of Parkinson’s disease Downloaded by [Cornell University Library] at 10:18 02 November 2017

Expert Rev. Neurother. 15(7), 723–732 (2015)

Elisa Unti, Roberto Ceravolo and Ubaldo Bonuccelli* 1 University of Pisa – Clinical and Experimental Medicine-Neurology Unit, via Roma 56, Pisa 56126, Italy *Author for correspondence: [email protected]

Apomorphine (APO) is a potent D1 and D2 dopamine agonist. Plasma maximal concentration is reached in 8–16 min with a plasma half-life of 34–70 min. Bioavailability is close to 100%. It has a rapid antiparkinsonian action after subcutaneous (sc.) administration with a size effect comparable with that of levodopa. Trials of sc., oral, sublingual, intravenous, rectal, intranasal and iontophoretic transdermal administration of APO have been attempted in Parkinson’s disease (PD), each of these routes have shown some potential for clinical effectiveness but the majority of studies indicate that APO intermittent sc. administration, on which this review is mainly focused, is an effective therapy for the management of motor symptoms in PD, particularly in advanced phases mainly characterized by motor fluctuations, such as wearing OFF and unpredictable “off”. Data on the effect of APO on non-motor symptoms in PD patients are limited but there is strong suggestion of a beneficial effect that warrants further investigation. KEYWORDS: apomorphine . disease . intermittent . motor fluctuations . Parkinson’s . subcutaneous . therapy

Overview of the market

Apomorphine (APO) is the oldest dopaminergic medication initially known for its emetic properties. It has been used as an analgesic, and has also been applied in several medical conditions, such as insomnia, alcohol dependence and schizophrenia. Parkinson’s disease (PD) is a common progressive neurodegenerative disorder affecting 20 in 100,000 people. The key structural neurodegenerative changes in the brain are loss of pigmented mesencephalic dopaminergic neurons projecting from the substantia nigra (pars compacta) to the neostriatum and the accumulation of protein a-synuclein into inclusion bodies (i.e., Lewy bodies) in neurons. Therefore, less dopamine is released into the neostriatum [1]. After the introduction of APO levodopa in the therapeutic arena, soon it was clear that approximately 5–10% of PD patients treated with levodopa develop dyskinesias and motor fluctuations, mainly represented by ‘off’ episodes occurring at the end of the levodopa dose (wearing-off phenomena) or at unpredictable times (on–off episodes). Off episodes are

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10.1586/14737175.2015.1051468

characterized by both motor and non-motor features that may include hypomobility, freezing, reduced dexterity, panic attacks, pain, behavioral changes or autonomic dysfunction. Off periods can result from ‘wearing off’ of the effect of oral medication and a return of symptoms before the next dose is taken, a delay in the time for a dose to adequately control symptoms (delayed “on”) or dose failures (no ON). Time To On (TTO) is now recognized as having a significant contribution to total off time: a study in 20 PD patients with motor fluctuations found that TTO was in fact more than twice the duration of wearing off [2] Off periods can occur frequently and may be unpredictable despite optimized oral medication, which impacts the patient’s daily routine and reduces their quality of life [3]. Gastrointestinal (GI) dysfunction is a common feature of PD and delayed gastric emptying has been identified as a likely causative factor in delayed ON of a levodopa dose [4,5] since it will prolong transit to its site of absorption in the small intestine. Impaired intestinal absorption of levodopa may also occur due to dietary protein – so called postprandial off – [6] or to bacterial overgrowth [7].

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Drug Profile

Unti, Ceravolo & Bonuccelli

Early morning off periods (morning akinesia) due to delayed TTO are common throughout the course of PD being reported in 58% of patients [3,8] but often go unrecognized. Oral treatment strategies to provide smoother dopaminergic stimulation involve modifying the pharmacokinetics of levodopa (catechol-O-methyl transferase [COMT] inhibition), dopamine availability in the CNS (monoamine oxidase-B [MAOB] inhibition) and the use of long-acting dopamine agonists. Despite optimum use of these strategies, complete control of motor fluctuations is seldom achieved and continuous stimulation by means of dopaminergic agent pump infusions (subcutaneous [sc.] APO and intraduodenal levodopa) or stereotactic surgery has been increasingly employed [9]. Overall the various ‘off’ complications in levodopa-treated patients with advanced PD are disabling and increase caregiver assistance time; they also are associated with recurrences of various non-motor features (anxiety, bladder and bowel problems, cognitive changes, pain, speech and swallowing difficulties) [10]. In additions to predictable early morning akinesia and wearingoff motor fluctuations, random ‘on/off’ episodes may occur over matter of seconds or minutes. Due to its short latency of effect via sc. administration, APO has been considered during the years as a good chance for the management of motor fluctuations. Introduction to the drug Chemistry & pharmacodynamics

APO is an aporphine derivative, very lipophilic and moderately soluble in water and normal saline [11], able to stimulate D1-like (D1, D5) and D2-like (D2, D3, D4) receptors, serotonin receptors (5HT1A, 5HT2A, 5HT2B, and 5HT2C) and a-adrenergic receptors (a1B, a1D, a2A, and a2C) [12]. Pharmacokinetics & metabolism

It has a very rapid onset of action combined with a brief duration of effect. The duration of APO action, after a single administration, is dose and mode of administration dependent, with an elimination half-life ranging from 30 to 90 min. The drug absorption, volume of distribution, plasma clearance and half-lives are similar for sc. injection, sc. infusion and intravenous (iv.) infusion, although it should be noted that the variation in absorption is high between subjects but low within individual subjects. Its high lipid solubility leads to transient APO brain concentrations, which can be up to eight-times higher than those in plasma [13]. The t1/2 after sc. injection is short – approximately 35 min. The tmax is about 10 min and onset of effect evident within a few minutes. Bioavailability is 100% [14]. Oral administration is not recommended because of APO’s significant first-pass hepatic metabolism and poor bioavailability.

due to its reported positive effects on surgically induced experimental decerebrate rigidity, Schwab et al. [15] successfully used sc. doses of APO at 0.5–1.0 mg to treat several PD patients. In the seventies, the group of Cotzias demonstrated that sc. APO had an effect on parkinsonian symptoms similar to levodopa [15,16]. However, the introduction of levodopa and the APO powerful emetic properties determined an eclipse in its therapeutic use. In Europe and many other countries, oral domperidone was successfully used as originally suggested by Corsini et al. [17], as pretreatment prophylaxis against nausea and vomiting induced by APO and other oral dopamine agonists. Subsequently, sc. APO was then proposed even as a diagnostic tool to distinguish between PD and other neurodegenerative parkinsonisms. Bonuccelli et al. after domperidone medication, administered 10, 50 and 100 mg/kg of APO versus placebo in 37 patients with parkinsonian syndromes and evaluated motor response for 90 min after each dose; 27 patients showed positive response without any difference between the dose of 50 and 100 mg/kg. After an adequate period of levodopa therapy (12-month follow up) 29 patients improved; 25 of these had demonstrated a positive response to APO test. The final diagnosis of idiopathic PD, made on the basis of an exhaustive clinical and neuroradiological evaluation and the response to chronic levodopa therapy, was in good agreement with the response to the APO test [18,19]. Roth et al. [19] studied 39 patients presenting with parkinsonian signs, 23 diagnosed as probable PD and 16 diagnosed as probable atypical parkinsonism. After an overnight withdrawal of all other dopaminergic drugs and domperidone medication, a single dose of sc. APO corresponding to 50 mg/kg of weight was administered. A marked clinical improvement, that is, at least 30% decrease of pre-treatment motor score values on Columbia University Rating Scale in 19 of 23 PD and 1 of 16 Parkinsonian Syndromes was observed; in PD group, the difference between motor score before and after sc. APO was highly significant (p < 0.001). These studies and other (review in [20]) lend support to the use of sc. APO as diagnostic test for PD. APO has been proposed even as a diagnostic tool for differentiating the type of levodopa induced abnormal involuntary movements (AIM). Considering that AIM may be classified into three main categories: ‘On’ dyskinesias, diphasic dyskinesias, and ‘off’ periods dystonias, the group of Obeso studied 168 advanced PD patients, observing a fairly good correlation between type of AIM and motoric status: chorea-like dyskinesias occurred during the ‘on’ period, while dystonias, particularly affecting the feet, were mainly present in the ‘off’ period; a few patients had a diphasic presentation. Acute pharmacological tests using dopamine agonists (sc. APO 3–8 mg; iv. lisuride 0.1– 0.15 mg) were performed in 40 patients showing that sc. APO enhanced ‘on’ dyskinesias and markedly reduced or abolished ‘off’ period dystonia and diphasic dyskinesias [21].

Clinical efficacy

The first use of APO (Apokin US-Bertek Pharmaceuticals, Apo-go Europe-Britannia Pharmaceuticals, Apofin Italy-Chiesi Pharmaceuticals) in treating PD goes back >60 years ago when, 724

Phase II study

After the pioneering study by Hardie et al. (1984) [22], Stibe et al. (1988) treated 19 patients with PD disabled by Expert Rev. Neurother. 15(7), (2015)

Apomorphine hydrochloride for the treatment of Parkinson’s disease

Drug Profile

Table 1. Summary of open-label studies of the efficacy of sc. APO to treat motor fluctuations. Study (year)

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Hardie et al. (1984)

N. patients

8

Daily ‘off’ time

Mean APO dose/ mean daily dose

Before

1/NR

NR

Ref.

After

Absolute difference

NR

NR

[22] ‡

Stibe et al. (1988)

8

NR

6h

2.7 h

3.3 h

[23]

Poewe et al. (1988)

7

4.7/NR

4.9 h

1.8 h

2.9 h‡

[67]

Pollak et al. (1989)

6

2.25/9

4.7 h

1.7 h

3 h‡

[68]

‡

Poewe et al. (1989)

17

3.8/12.2

4.7 h

1.7 h

3h

[69]

Kempster et al. (1990)

14

2/2

NR

NR

NR

[24]

Frankel et al. (1990)

30

2.2/10.2

6.9 h

2.9 h

4 h*

[28]

Hughes et al (1991)

15

3.4/NR

NR

NR

NR

[70]

NR

NR

NR

Hughes et al. (1991)

7

†

2.7/34.3

[71] ‡

Hughes et al. (1993)

49

2–5/11.7

6.2 h

3.6 h

2.6 h

[29]

Deffond et al. (1993)

7

4.1/13.1

40% of waking day

18% of waking day

22% of waking day*

[63]

Gervason et al. (1993)

10

81 mg/Kg/NR

NR

NR

NR

[72]

Pietz et al. (1998)

24

1.9/9.7

50% of waking day

29.5% of waking day

20.5% of waking day

[30]

†

Mean of 12.7 APO injections over 10 h (2.7 mg/dose). Statistical comparison not reported. *p < 0.02 APO: Apomorphine; NR: Not reported or results could not be derived from available data. ‡

severe on–off fluctuations with continuous infusion during the day or by repeated injections (TABLE 1). The 11 patients treated by infusion showed marked and sustained improvement, and their mean duration of daily ‘off’ periods over a period of 15 months fell by 6.3 h; similar results were obtained in eight patients with less severe disabilities who were given repeated sc. APO injections [23]. In an open-label study, Kempster et al. [24] compared motor response to APO to that of levodopa in 14 PD fluctuating, with a mean duration of levodopa therapy of 9.8 years. Before administration of study drugs, all antiparkinsonian medications were withheld overnight. The following morning patients were given a single dose of levodopa (250 mg) and on the second day, a single sc. dose of APO (mean dose 2 mg). All patients received domperidone (20 mg) 2 h before administrations of APO. The amplitude of motor response, or the change from predose ‘off’ state to the best ‘on’ state, was similar between APO and levodopa. However, compared with oral levodopa, sc. APO was associated with a shorter duration of effect (mean 56 min APO vs 211 min levodopa) but a faster onset of effect (7.9 vs 35.4 min, respectively). Van Laar et al. [25] selected five patients with idiopathic PD with severe response fluctuations for a randomized, doubleblind, placebo-controlled study, concerning the clinical effects of sc. APO and its assessment in ‘off’ periods (TABLE 2). The effect of APO was evaluated using the Columbia Rating Scale

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and quantitative assessments, using tapping, walking and pinboard. There was a significant positive effect of APO, with a mean optimal dose of 2.7 mg, with a mean latency of onset of 7.3 min and a mean duration of response of 96 min. All patients were medicated with domperidone and no significant adverse effects were observed. Effects, therapeutic dose range, and pharmacokinetics of APO, given as sc. injections by a single use pen, were evaluated by Ostergaard et al. in the treatment of ‘off’ phenomena in 22 patients with idiopathic PD. At study entry, a placebocontrolled APO test was performed, and APO doses were then individually titrated (mean 3.4 [range 0.8–6.0] mg) and compared with placebo in a double-blind crossover phase. When comparing APO with placebo, the mean daily duration of ‘off’ periods was reduced by 51% as assessed by the patients and by 58% as assessed by the staff. The severity of ‘off’ periods was also significantly reduced. The effect was unchanged after a maintenance phase of 8 weeks. At study termination, 13 of 14 patients were able to inject themselves and 11 of 14 patients found that their feeling of freedom from symptoms had increased [26]. Similar data were found in a prospective, double-blind, placebo-controlled crossover study conducted by Merello et al. [27]; 12 PD with motor fluctuations were randomized to receive sc. APO (3 mg) or oral levodopa (250 mg) on consecutive days on a double-blind basis. A similar amplitude of effect was 725

Drug Profile

Unti, Ceravolo & Bonuccelli

Table 2. Summary of double-blind studies of the efficacy of sc. APO to treat motor fluctuations.

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Study (year)

Study design

N. patients

Primary end point

Cotzias et al. (1970)

CO, PC

15

Disability Score

Van Laar et al. (1993)

CO, PC

5

Ostergaard et al. (1995)

CO, PC

Merello et al. (1997)

Change in primary end point Without APO

Ref.

With APO

Absolute difference

NR

NR

10–15% pts improved >20% from baseline

[16]

Columbia Parkinson’s Disease score

Placebo: –0.4

APO: –6.4

6**

[25]

22

‘Off’ time during awake times

Baseline: 7.4 h

4.2 h

3.2 h*

[26]

CO; comparator, Levodopa/ Benserazide

12

Change in modified Webster disability score

Baseline 23.3

11.9

11.5*

[27]

Dewey et al. (2001) APO 202 Phase I

PG, PC

29

Change in UPDRS motor score

Baseline 39.7

15.8

23.9*

[31]

Dewey et al. (2001) APO 202 Phase II

PG, PC

26

‘Off’ time

Baseline 5.9 h

3.9 h

2.0*

[31]

APO 301 (see in Stacy&Silver,2008)

PC, CO

17

Change in UPDRS motor score at 20 min

Placebo: –3

APO: –20.0

17*

[33]

Pahwa et al. (2007) APO 303

PG, PC

56

Change in UPDRS motor score at 20 min

Placebo: –2.8

APO: –11.2

–9.6/–15.5

[34]

Trosch et al. (2008)

CO, PC

51

Change in UPDRS motor score at 20 min

Placebo: –2.8

APO: –11.2

8.4*

[35]

*p < 0.001. **p = 0.001. APO: Apomorphine; CO: Crossover; NR: Not reported or results could not be derived from available data; PC: Placebo; PG: Parallel group; UPDRS: Unified Parkinson’s Disease Rating Scale.

observed for both APO and levodopa. APO was associated with a more rapid onset of effect compared with levodopa and a shorter duration of effect. Several studies then examined the results of long-term intermittent sc. APO. Frankel et al. administered sc. APO to 57 levodopa-treated PD patients with refractory ‘off’ period disabilities for a median duration of 16 months. In 30 patients, receiving intermittent injections the mean number of hours spent in a disabling ‘off’ state fell from 6.9 to 2.9 h. Similar benefit was observed in 21 patients receiving continuous infusions with additional boluses on demand by mini-pump (mean reduction of hours ‘off’ from 9.9 to 4.5). Twelve patients have been treated for over 2 years without tachyphylaxis or loss of response. The incidence of neuropsychiatric side-effects was low (7%). Six patients failed to show a sustained worthwhile response; severe disabilities during ‘on’ periods being the major problem [28]. In another long-term study, sc. APO was administered – either by continuous waking-day infusion with boluses or by repeated intermittent injection – to 71 PD patients with severe 726

refractory levodopa related on–off fluctuations for 1–5 years. A mean reduction in daily ‘off’ period time of approximately 50% was maintained, and the incidence of neuropsychiatric toxicity remained low on the long-term follow-up. No clinically significant tolerance or loss of therapeutic effect was seen, although increasingly severe on-phase dyskinesias and postural instability marred the long-term therapeutic response in many patients [29]. Another study investigating the therapeutic response during long-term treatment with APO included 49 advanced PD patients treated for a maximum of 66 months with intermittent sc. injections or continuous infusions of APO. Most of the patients experienced a long-term symptomatic improvement. The time spent in ‘off’ was significantly reduced from 50 to 29.5% with intermittent injections and from 50 to 25% with infusions of APO. The quality of the remaining ‘off’ periods was improved with infusion treatment, but was relatively unaffected by APO injections. The overall frequency and intensity of dyskinesias did not change. The therapeutic effects of APO were stable over time [30].

Expert Rev. Neurother. 15(7), (2015)

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Apomorphine hydrochloride for the treatment of Parkinson’s disease

Three USA pivotal, prospective, randomized, placebocontrolled clinical trials have assessed sc. APO as acute treatment for ‘off’ episodes in patients with idiopathic PD. The first trial (APO202) enrolled APO-naı¨ve patients with advanced PD, who experienced at least 2 h ‘off’ time per day (mean 5.9 h in each treatment group) despite optimized oral drug therapy [31]. During the initial inpatient phase, ‘off’ episodes were induced by withholding morning doses of oral PD therapy, and response to APO or placebo at increasing doses was observed. APO dosage was initiated at 2 mg and increased in 2 mg increments to a maximum of 20 mg. In the 1-month outpatient phase, patients or caregivers administered APO or placebo as needed (up to five-times per day) to treat spontaneous ‘off’ episodes, motor assessments were performed 15–20 min after injection of the study drug. The primary efficacy endpoint was the change in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score from pre- to post-dose, which was assessed at the highest titration dose achieved. During the outpatient phase, patients completed daily diaries. The other two trials were conducted in APO-experienced patients. APO301 was a randomized, placebo-controlled crossover study evaluating the durability of response to APO in 17 patients who had previous stable exposure to APO of at least 3 months. At a mean APO dose of 4 mg per injection, UPDRS motor scores at 10–20–60 min after injection were significantly improved from the pre-dose assessment. In the APO 302 trial, patients received one of the four following treatments: APO at the patient’s typically effective dose; APO at the typically effective dose plus 2 mg (0.2 ml); placebo at an equivalent volume to the typically effective dose of APO, or placebo at an equivalent volume to the typically effective APO dose plus 0.2 ml [32]. There were no significant differences between groups in patient baseline characteristics in all three trials, following an APO injection patients were asked to declare or record the time at which they received a significant improvement in condition to calculate the time to onset of action. After approximately 20 min in all three trial, the mean improvement from baseline in UPDRS motor score was significantly better with APO than placebo [31,32]. In the trial in APOnaive patients (APO202), APO successfully treated 95% of the ‘off’ events it was used for (compared with 23% with placebo; p < 0.001) and reduced the number of ‘off’ hours per day by 2 h (compared with no change with placebo; p = 0.02) [33]. These pivotal studies led to the approval by the US FDA in 2004 of APO sc. injection as intermittent treatment for acute off phases in PD. To further explore the long-term efficacy and safety of sc. APO in treating ‘off’ episodes, Pahwa et al. [34] selected 56 patients receiving optimized oral anti-PD medication (APO 303 study). These patients were evaluated on separate days for response to single increasing doses of APO. Acute response to oral anti-PD medication and APO dose escalation (2–10 mg) was evaluated under unblinded conditions. At the 4 mg APO dose, placebo was randomly introduced under double-blind crossover conditions. Mean changes from pre-dose in UPDRS informahealthcare.com

Drug Profile

motor scores indicated significant improvement following APO 4 mg versus placebo at 20 (p = 0.0002), 40 (p < 0.0001; maximum improvement) and 90 min (p = 0.0229). Improvements showed significant dose–response at 20, 40 (both p < 0.0001) and 90 min (p = 0.0049). The outpatient follow-up phase of the APO 303 study assessed the long-term efficacy and safety of intermittent sc. APO for ‘off’ episodes in patients with advanced Parkinson’s disease. Patients received APO at a dose considered optimal based on safety and efficacy assessments during the dosetitration phase. Outpatient evaluation visits were scheduled at 1 and 2 weeks, and 1, 4 and 6 months. Efficacy parameters included changes in UPDRS. APO significantly (p < 0.05) reduced UPDRS motor scores at 20, 40 and 90 min post-dose versus pre-dose at all evaluation visits [35]. Phase III–IV study

Finally, a very large study evaluated long-term safety and adverse events of sc. APO doses (2–10 mg/dose) administered for at least 12 months in 546 fluctuating PD patients. The majority of patients used APO on a daily basis; the average dose was 4.0 mg. A total of 187 subjects discontinued treatment because of adverse events, most of them mild to moderate and expected with APO: nausea and vomiting, dyskinesia, dizziness, somnolence, hallucinations, yawning and injection site bruising. Serious adverse events occurred in 199 patients but only in 27 cases were considered to be probably or possibly treatment related. None of the deaths recorded in the study were attributed to APO [36]. Preliminary results for the first 50 patients of an ongoing Phase IV, multicenter, open-label study (Apokyn for Motor IMProvement of Morning AKinesia Trial) have demonstrated a more rapid and more reliable TTO with APO injection compared with the usual oral morning levodopa dose – 95% of patients achieving at least a 20-min reduction in TTO with an average reduction of ~40 min. Dose failures were common with oral levodopa but not after APO injection [37]. Continuous sc. APO infusion therapy has proven to be effective in advanced PD patients with motor fluctuations not controlled by oral medication. APO is delivered by a portable syringe driver, usually for 12–16 h per day with the aim of reducing oral medication as much as possible to avoid pulsatile therapy. In practice, most patients remain on a small dose of levodopa, particularly to cover night-time when the APO infusion is not running. Efficacy of continuous sc. APO infusions in monotherapy or as an add-on to levodopa therapy in advanced PD has been evaluated in numerous clinical trials; these studies proved that APO sc. infusion is successful in decreasing ‘off’ periods, reducing dyskinesias and improving PD motor scores with the added benefit of a substantial levodopa-sparing effect [38]. Continuous sc. APO infusion has been compared with levodopa infusion in an open-label study on 87 PD patients. Patients in the APO group (43) showed moderate improvement on Non Motor Symptom Scale associated to a robust 727

Drug Profile

Unti, Ceravolo & Bonuccelli

improvement in motor symptoms and complications; particularly, APO showed a significantly greater effect on mood and apathy symptoms. Only four new cases of impulse control disorder, none of them requiring discontinuations of therapy developed in APO group [39].

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Subcutaneous intermittent APO for non-motor symptoms in PD

While there is a reasonable body of evidence that confirms the efficacy of APO on motor function in PD, there have also been sporadic reports of the possible beneficial effect of APO on non-motor symptoms (NMS) in PD. NMS affect most patients with PD and often has a profound impact on their quality of life. Some of them, such as depression, anxiety, fatigue, rapid eye movement sleep behavior disorder, constipation, delayed gastric emptying, altered olfaction and pain can even precede the onset of motor symptoms. Other NMS, including hallucinations, dementia, excessive daytime sleepiness, insomnia, orthostatic hypotension and bladder disturbances, typically appear later in the course of PD [40]. Regarding gastrointestinal symptoms, constipation is one of the most common non-motor features of PD, to date very few studies have investigated the effects of APO. In 1989, exploring striated anal sphincter function electrophysiologically and radiologically in PD patients, Mathers et al. [41] found functional improvement of the defecatory mechanism after the administration of APO in four of six patients. In another study, a specific defecating proctogram and anorectal manometric study before and after the administration of sc. APO was evaluated in eight subjects with PD: the results showed that APO could restore a correct anorectal function suggesting that the defecographic abnormalities found before APO could be a consequence of dopaminergic central deficit [42]. Recently, Rossi et al. [43] reviewed literature confirming that when due to pelvic floor dyssynergia, constipation may benefit from APO injections. Also swallowing disorders have been considered a possible consequence of dopaminergic impairment and the effects of APO on liquid swallowing using video fluoroscopy have been studied in advanced PD patients with some improvement in swallowing abnormalities and total swallowing time reduction [44]. Sleep disturbances are extremely common in PD and mainly represented by initial insomnia, sleep fragmentation, sleep maintenance insomnia and periodic limb movements but unfortunately only few studies have considered APO effects in this area. A single case of a 66-year-old woman with severe sleep problems, including reversal of circadian rhythm, successfully treated with nocturnal sc. APO infusion has been reported [45]. A rapid and significant (55%) improvement in symptoms and an almost immediate cessation of periodic limb movements has been observed after APO iv. in a group of patients with restless leg syndrome [46] and in another study in patients with periodic limb movement during sleep; 0.5 mg sc. APO at bedtime were able to ameliorate this disorder [47]. In a group of 12 PD patients, one night’s treatment with a new 728

transdermal formulation of APO improved akinesia, rigidity and periodic limb movements [48]. APO was found to improve urinary function in PD patients who very often complained of nocturia: 10 PD patients underwent urodynamic assessments before and after sc. administration of APO. Voiding efficiency improved after APO injection, with an increase in mean and maximum flow rates in nine patients and reduction in post-micturition residual volume in six of them, suggesting that sc. APO may be useful in the treatment of voiding dysfunction in PD [49]. No proper studies have been undertaken showing the relation between APO and impulse control disorders (ICDs). Only one small study by Magennis et al. [50], an audit of APO use in Ireland, showed improvement of ICDs in five patients after they were commenced on APO infusion. In a recent observational study by Todorova et al. [51], of 41 patients receiving APO infusion, seven had pre-existing ICDs that resolved or attenuated after the initiation of therapy. Six new ICDs developed, including excessive eating, compulsive shopping and internet use, hypersexuality and punding, but in two cases, patients were on dual agonist treatment with rotigotine and thus the relationship of the ICD with APO was unclear. The authors concluded that APO infusion appears to have a relatively low risk for the development of ICD, with discontinuation of therapy required only in 2.4%. This finding on low rates of ICD on APO is also indirectly supported by a large scale multicenter national study conducted by Garcia-Ruiz et al. [52] of 82 patients on chronic APO infusion therapy. At a mean follow-up period of 19.9 ± 16.3 months, only one had developed severe hypersexuality, whereas the overall rate was 8%. These preliminary studies, currently largely restricted to abstract based and open-label information, suggest a substantially lower rate of development of ICDs in moderate-toadvanced PD with the use of continuous drug delivery strategy for at least 14–24 h a day using APO infusion. This observation needs to be examined in a controlled manner with largescale international studies. Subcutaneous intermittent APO side effects

Adverse events are usually mild and consist predominantly of cutaneous reactions and neuropsychiatric adverse effects. The incidence of adverse effects is higher in patients receiving continuous infusion than in those receiving intermittent pulsatile administration [38]. In the three pivotal studies (APO202, APO301, APO302), most adverse events experienced by patients in APO group were mild in severity; injection site complaints, including bruising, pain, skin reaction, and development of nodules, were common in both APO (45%) and placebo (56%) recipients. The only adverse events that occurred at a significantly higher incidence in the APO group than the placebo group were yawning (40% vs. 0%; p = 0.03) and drowsiness or somnolence (35% vs. 0%; p = 0.07) [31,32]. Neuropsychiatric side effects often complicate dopaminergic therapies and pose a significant problem in the optimal Expert Rev. Neurother. 15(7), (2015)

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Apomorphine hydrochloride for the treatment of Parkinson’s disease

management of PD. Several articles report a relative lack of neuropsychiatric side effects in PD patients treated with sc. APO. Although considered to be the most potent dopamine receptor agonist, APO has been shown to be unable to activate schizophrenic symptoms or to induce psychosis in nonschizophrenics [53]. By a closer scrutiny of the series of Stibe et al. [23], it can be observed that psychosis that was present in patients on oral dopaminergic treatment did not recur when patients were switched to sc. APO. To investigate this further, Ellis et al. [54] conducted an open-label study on 12 PD patients selected for intolerance to oral therapy because of neuropsychiatric complications including psychosis. The rescue sc. system was used in 5 of 12 patients who were able to predict off periods: when stabilized on sc. APO, an abolition or a reduction of neuropsychiatric complications and a significant improvement in off periods (>60% reduction in off periods) in all patients was noticed. Nausea and vomiting can occur in PD patients initiated on sc. APO injections and antiemetic prophylaxis is recommended per product labeling. Data suggest long-term antiemetic prophylaxis may not be needed, although this has not been systematically studied. During the 1980s, reports of cardiac arrest, ventricular arrhythmia (VA) and sudden death associated with the use of iv. domperidone, often administered with other medications with known cardiac side effects, led to market withdrawal of the iv. formulation [55–58]. Concern about the cardiotoxicity of oral domperidone has arisen more recently; in 2010, Johannes et al. conducted a case–control study nested in a retrospective cohort evaluating the combined risk of serious ventricular arrhythmia (SVA) and sudden cardiac death (SCD) in users of domperidone compared with users of proton pump inhibitors (PPIs), or non-users of these medications. From 83,212 individuals in the exposure cohort, 1608 cases were identified, 49 SVA and 1559 SCD (mean age 79.4 years, females 52.9%, diabetes 22.3%) and 6428 matched controls. The adjusted odds ratio for SVA/SCD with current domperidone use compared with non-use was (1.59, 95% CI: 1.28– 1.98), or compared with current PPI use was (1.44, 95% CI: 1.12–1.86). In stratified analyses, adjusted ORs were numerically higher in males, older subjects and non-diabetics. The increased risk of SVA/SCD for current domperidone users remained after adjustment for multiple covariates [59]. These results suggest that domperidone doses lower than 40 mg/day should be used and caution needs to be exercised in those greater than 60 years of age with close monitoring of cases on high dose oral domperidone [60]. In countries, where domperidone is not routinely available, alternative antiemetics may need to be used. Skin reactions occur frequently in continuous APO infusion, less frequently in intermittent sc. administration and may sometimes interfere with the absorption of therapy [61]. The histopathology of APO-induced skin reactions is poorly understood, histological skin tissue characteristics are presence of informahealthcare.com

Drug Profile

eosinophils, melanin-like pigment, fibrosis, lymphocytes and histiocytes. Therefore, treatment options are limited and suggestive, usually local steroids are useful. However, several longterm studies as well as cumulative clinical experience of several centers in Europe, with long-term experience in APO therapy, report that skin nodules are seldom a reason for discontinuation of therapy as long as good skin hygiene is followed. Intermittent sc. APO is an efficacious therapy in advanced PD for aborting and/or decreasing ‘off’ periods. A limiting factor for the use of APO is represented by nausea and retching. In the USA, trimethobenzamide is the only recommended antiemetic for use in PD because it does not have significant central dopamine antagonistic effects. Using a controlled design, with phased withdrawal of subjects from trimethobenzamide to placebo, this drug has been very recently evaluated in 182 PD patients co-administered with APO. Trimethobenzamide helps reduce nausea/vomiting during the first 8 weeks of APO therapy, but is generally not needed thereafter, and does not worsen parkinsonism nor affects ‘on’ response after APO injection [62]. Safety & clinical experience with other pharmaceutical forms

In 1993, Deffond et al. evaluated the efficacy of sc. and sublingual (sl) APO in seven PD patients with motor fluctuations, comparing the reduction of total daily ‘off’ phases. The study was divided into two parts. In the first part, all patients were treated with intermittent sc. injection of APO; in the second part, after the treatment with sc. injection was stopped, APO was administered sublingually. For each route, APO was given during an ‘off’ period, and the dose was progressively increased until the optimal effective dose in each patient was obtained. All patients showed a striking improvement with APO treatment, expressed by reduction of diurnal time spent in ‘off’ phase both with sc. and sl administration; the effective sl dose (630 mg/kg) was about 10-fold higher than the effective sc. dose (61 mg/kg). This poor bioavailability could be partially explained by the time needed for the dissolution of the tablet, probably leading to the swallowing of a part of the administered dose. Different to oral administration, no case of uremia was observed since lingual mucosa is drained by systemic circulation and not by the portal vein. The most frequent side effect reported in sl administrations was stomatitis in two of seven patients after 2 months of therapy: the conclusion was that sl APO could be useful for treatment of PD; however, it was strongly limited by local side effect and latency of onset of motor benefit [63]. Few years later, Dewey et al. proposed intranasal APO administration in advanced PD patients as rescue therapy for parkinsonian off states. Authors concluded that intranasal APO could be an effective rescue agent for PD, although limited by nasal irritation reported in five of nine patients [64]. More recently, Grosset et al. [65] conducted an open-label, placebo-controlled study on 24 PD patients showing that inhaled APO at dosage of 0.2, 0.5 and 0.8 mg was well tested but motor effects were limited. 729

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Unti, Ceravolo & Bonuccelli

In summary, sl and intranasal APO administration have been progressively abandoned mainly due to local side effects, while sc. administration has become a therapeutic strategy in advanced PD.

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Expert commentary

Since its first use in 1951, APO has shown efficacy on motor symptoms, less is known about the efficacy on non-motor symptoms, reducing motor fluctuations off times leading to a better quality of life. Careful patient selection by experienced specialist neurologists further improves effectiveness and minimizes adverse effects that can lead to unnecessary cessation of therapy. However, patients and caregiver’s have to be provided with adequate education and support, ideally by a specialist nurse. APO is an excellent drug that nonetheless is underused. This may be due to the minor technical complications involved and because it requires more skill from the patient. Five-year view

In front of the large evidence of sc. APO efficacy on motor symptoms, less is known about efficacy on non-motor symptoms. Clinical experience supported by case reports or openlabel studies suggest beneficial effect on sleep dysfunction, gastrointestinal problems (i.e., constipation), urinary dysfunction and impulse control disorders [66]. All these aspects need to be studied in specifically designed double-blind studies in which primary end point should be NMNs. Another aspect that should be implemented for patients candidate to sc. APO therapy is represented by a kind of ‘APO school’ where patients should be educated, particularly teaching

how to administer sc. injections and how to prepare injection site. This could further limit local reactions, albeit mild and rare when comparing intermittent injection to continuous infusion, which may, however,induce the patient to treatment discontinuation. Another goal of the APO school might be to explain the phenomenon of tolerance to emetic effects, teaching how to titrate the drug slowly, starting from sub-emetic doses for reaching higher doses effective on motor symptoms without nauseating effects. Information resources

In this review, articles were selected on PubMed using the following keywords ‘APO,’ ‘APO in Parkinson Disease,’ ‘APO in Parkinson’s Disease,’ ‘APO treatment strategies.’ Motor efficacy of APO is similar to levodopa as shown in an old open-label study conducted on non-PD fluctuating patients [24]. The three USA studies conducted between 2001 and 2008 [31–34] showed efficacy and safety of sc. APO in controlling ‘off’ episodes in PD patients, the most frequent side effects reported were yawning, drowsiness, or somnolence. Motor effects of APO have been further confirmed by LeWitt et al. [36] in long-term study on 546 PD fluctuating patients. Financial & competing interests disclosure

U Bonuccelli has received research funding from Lundbeck and UCB Pharma Italy and board fees from Zambon Pharma Italy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues . .

Apomorphine (APO) is a dopamine agonist with motor efficacy similar to levodopa. APO subcutaneous injections are very efficacious in treating ‘off’ episodes in Parkinson’s disease, being able to reverse motor symptoms completely in a matter of min.

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APO subcutaneous may show beneficial effect even on non-motor symptoms, such as sleep dysfunction, gastrointestinal problems and urinary dysfunction.

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Further investigations are needed to evaluate the effect of APO in neuropsychiatric symptoms.

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The treatment can be initiated during in-patient hospitalization or in a day hospital setting.

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Patient’s and caregiver’s education and support in handling the device have to be provided, ideally by a specialist nurse.

OFF motor fluctuations. Clin Neuropharmacol 2003;26:196-8

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Apomorphine hydrochloride for the treatment of Parkinson’s disease

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Drug Profile

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