Part 2 Apomorphine for Parkinson’s Disease: Efficacy and Safety of Current and New Formulations

Safety

Apomorphine is usually well-tolerated, and adverse events range from mild to moderate in intensity. Overall, the incidence of adverse events seems to be generally higher in patients receiving CSAI than in those treated with intermittent injections [79].

Cutaneous and subcutaneous adverse reactions—including bruising, subcutaneous nodules and, rarely, necrosis or abscess formation at injection or infusion sites—are the most common, followed by nausea and somnolence. Histologically, subcutaneous nodules present as infiltrates containing eosinophils, lymphocytes and histiocytes as well as melanin-like pigments and, in chronic conditions, fibrosis [80, 81]. Although these cutaneous reactions are usually mild, they can, in rare cases, lead to drug discontinuation because of abscess and necrosis. This risk can be reduced by ensuring thorough skin hygiene, using new needles for each injection, changing the site of injection and using localized massage and ultrasound therapy [82].

Nausea and vomiting in response to apomorphine can be controlled with preventive temporary administration of antiemetics (such as domperidone or trimethobenzamide) [27]. Nausea, vomiting and hypotension mainly occur at initiation of apomorphine, where they seem to be more common in patients treated with intermittent subcutaneous apomorphine than with CSAI [47].

Sedative effects are also common with apomorphine, whereas other central dopaminergic side effects such as confusion, hallucinations and psychosis are less commonly observed than with oral dopamine agonists. The latter may be related to differences in the dopamine receptor subtype affinity of apomorphine [72]. Data on the relationship between apomorphine and ICDs are limited. Binge eating, compulsive sexual disorder and punding have been reported, but the incidence of ICDs seems to be low, with only rare cases requiring discontinuation of CSAI [72, 83, 84].

Hematologic adverse events are a rare complication of apomorphine therapy, but the risk of developing autoimmune hemolytic anemia in patients undergoing CSAI should be appropriately monitored with regular blood cell counts, checks of hemolytic parameters and Coombs test to detect antibodies targeting red blood cells. How frequently these tests should be performed during chronic treatment with apomorphine is somewhat controversial. The mechanism responsible for this autoimmune response remains unclear [85].

Apomorphine has been reported to induce QT interval prolongation in post-marketing surveillance [110]; however, no evidence yet shows a direct link between drug administration, QT prolongation and cardiac arrest. Conversely, apomorphine may have a broader cardiovascular safety margin than originally thought [111].

Safety results from controlled trials of intermittent subcutaneous apomorphine injections reveal a generally mild-to-moderate adverse event profile. In the APO202 study, adverse event rates were almost identical between the placebo and the apomorphine group (89 vs. 85%), and events were almost all classified as treatment-emergent adverse events (TEAEs). Events only reported in the apomorphine group were yawning (40%) and somnolence (35%) [54]. Dyskinesias as an adverse event were reported in 35% of the apomorphine-treated subjects versus 11% of the placebo group. During the inpatient phase of this trial, nausea was reported in 30% of subjects receiving apomorphine, whereas this was almost never the case in the subsequent outpatient phase. All study participants received trimethobenzamide as antiemetic prophylaxis.

APO401 was a large open-label study (n = 546) assessing the long-term safety of intermittent subcutaneous apomorphine [33]. During the 12-month treatment period, 93% of all patients with PD in the study experienced at least one adverse event. Most of these events were regarded as mild or moderate in severity. The most common TEAEs were nausea and vomiting (33%), falls (33%), dyskinesias (24%), dizziness (22%), somnolence (21%), hallucinations (19%), yawning (16%) and injection site bruising (15%). A total of 187 patients discontinued treatment because of adverse events. Serious adverse events were reported in 199 (36.4%) patients, but most were considered only remotely related or definitely unrelated to apomorphine. In total, 19 patients experienced 27 serious adverse events that were possibly or probably related to apomorphine. Among these 27, the most common were syncope (n = 3), drug-induced psychosis (n = 3), postural hypotension (n = 2) and falls (n = 2). Safety assessment from the only placebo-controlled trial with CSAI (TOLEDO) reported adverse events in line with the evidence presented by previous observational studies [45]. Apomorphine infusion was well-tolerated, and no unexpected safety signals were observed in this trial, with most of the adverse events being of mild or moderate intensity. Overall, 93% (50/54) of patients in the apomorphine group had at least one TEAE compared with 57% (30/53) of patients in the placebo group. The most common TEAEs were skin reactions (44 vs. 0%), nausea (22 vs. 9%) and somnolence (22 vs. 4%). Not surprisingly, neuropsychiatric TEAEs occurred more commonly in the apomorphine group (mild hypersexuality, n = 1; mild punding, n = 2; mild to severe confusion episodes, n = 1; moderate psychosis, n = 1; and mild to moderate hallucinations, n = 2) than in the placebo group (episodes of mild confusion, n = 2; mild hallucinations, n = 2). With dose reduction, almost all neuropsychiatric TEAEs were resolved. Six patients (11%) in the apomorphine and none of the placebo group withdrew from the study because of treatment-related adverse events. Half of the patients withdrew because of serious adverse events (severe orthostatic hypotension, n = 1; myocardial infarction, n = 1; abnormal persistent non-hemolytic hematology test results). The other patients withdrew because they experienced visual hallucinations (n = 1), moderate gait disturbance (n = 1) or mild infusion-site erythema (n = 1). All events leading to study withdrawal, except for myocardial infarction, were thought to be treatment related. Indeed, all were resolved after cessation of apomorphine.

Some possible drug–drug interactions should be considered with apomorphine treatment. These include the concomitant administration of apomorphine with 5HT₃ antagonists such as ondansetron, which may induce severe hypotension and syncope, and combination with drugs associated with QT/QTc interval prolongation, especially when domperidone is given for antiemetic prophylaxis. Indeed, domperidone may cause QT/QTc prolongation and is associated with increased risk of ventricular tachyarrhythmia and sudden cardiac death in patients with PD with preexisting cardiac disease [86]. Given the potential for cardiac side effects with domperidone, its use has been restricted by the European Medicines Agency [87].

Apomorphine should be used carefully in patients with orthostatic hypertension because its ability to lower systolic and diastolic blood pressure may aggravate symptoms.

When initiating apomorphine therapy, antiemetic prophylaxis and close medical supervision are recommended to maximize adherence.

Apomorphine in Parkinson’s Disease: Practical Considerations

Intermittent injections are a viable rescue medication for patients who are already optimized on oral medications and are still experience troubling “off” periods. Apomorphine injections can also be beneficial in patients with impaired gastric emptying that results in delayed levodopa absorption. Suitable candidates for intermittent apomorphine injections should be capable of injecting themselves or have a caregiver able to inject them when needed [88]. Exhaustive injection training (or pump training for patients starting continuous infusion) for patients and caregivers with a physician or a nurse experienced in the treatment of advanced PD plays a fundamental role in therapy compliance and in preventing adverse events. The injections are given via a multidose pen loaded with a solution of apomorphine hydrochloride 10 or 20 mg/mL. When beginning intermittent apomorphine injection therapy, the patient is asked to come to the clinic without taking their usual dopaminergic medications for dose titration; once the patient reaches an “off” episode in clinic, a first dose of apomorphine 2 mg should be administered. Time to onset of effect, duration of effect and adverse effects must be recorded during a monitoring period of 1 h from injection. Until the desired motor response is obtained, the dose can be increased by 1–1.5 mg; the optimal dose for most patients usually ranges from 2 to 6 mg and, once it is achieved, further dose adjustments over time are not usually required. The daily number of injections varies considerably between patients, but subjects who require more than five or six injections per day are usually recommended to switch to CSAI [88].

CSAI is administered via a portable pump system that delivers a continuous dose, with the possibility of releasing a rescue bolus if needed. The duration of infusion is normally 12–16 h (waking time), but a 24-h regimen can also be programmed for patients experiencing nocturnal hypokinesia [89]. Patients with PD who have “off” periods no longer controlled with optimized oral therapy or who need apomorphine rescue doses too frequently are suitable candidates for CSAI. The pump can also be an alternative to surgical therapy or to enteral levodopa infusion [90]. For patients starting CSAI in the inpatient setting, domperidone 10 mg (or trimethobenzamide in countries where domperidone is not available) three times daily from 1 day before initiation to 3–7 days in total is strongly recommended to prevent nausea [90]. On the first day, apomorphine treatment is started at a dose of 0.5 or 1 mg/h. Uptitration is usually with 0.5 or 1 mg/h daily increments, and the optimal infusion rate ranges from 4 to 7 mg/h for most patients. Concomitantly, oral dopamine agonists and other antiparkinsonian drugs are gradually discontinued. During the titration phase, levodopa is also usually reduced, and discontinued if possible in patients with dyskinesia [90]. The same uptitration protocol should be used for outpatients but with a slower increase in infusion rates.

Alternative Apomorphine Delivery Strategies

To date, the main administration route for apomorphine in PD has been subcutaneous, either as a continuous infusion or as an intermittent pen injection. This route has proven effective, but skin reactions are among the most common adverse events and can complicate treatment or lead to withdrawal. For some patients, this delivery may also be problematic because of needle phobia; for others, the pen injection may prove challenging for resolving an acute “off” phase because of bradykinesia and tremor. Despite its remarkable efficacy, apomorphine suffers from the lack of an “easier” and less invasive delivery system. Several alternative delivery routes have therefore been tested, and some are in active clinical development.

Pulmonary delivery of drugs has the potential of very rapid entry into the systemic circulation through the lung’s extensive alveolar surface with no hepatic first-pass effect, making it an attractive strategy to achieve rapid onset of effect to “rescue” patients from “off” periods. An apomorphine powder formulation for delivery via an inhaler device (VR040) has been developed and used in a single-center, placebo-controlled, randomized study in patients with motor fluctuations. Inhaled apomorphine proved to be well-tolerated, but efficacy was limited [91]. Two larger studies followed, in which the drug proved to have rapid absorption (2–7 min) mirrored by a rapid clinical reversal from the “off” state (10 min) [92, 93]. These short-term studies reported no pulmonary safety concerns, but no reports of further clinical development of this agent have been released.

Oral apomorphine is considered infeasible because of the almost complete first-pass hepatic metabolism of the molecule [35]. However, the administration of apomorphine and its prodrug (dipalmitoyl apomorphine) via oral lipid-based formulations has recently been reported in animal models of PD. This formulation is still in the preclinical phase but may have the potential to achieve steady dopaminergic stimulation because of its sustained drug release [94].

Sublingual formulations of apomorphine have been recognized as a viable alternative to the subcutaneous route for decades [95–97]. A sublingual formulation needs no needles, causes no pain and is easily administered, even during a severe “off” phase. A novel sublingual apomorphine formulation consisting of a two-film strip that contains apomorphine in a bilayer (APL-130277) has been shown to reliably revert “off” periods in several clinical trials. A proof-of-concept study for this new formulation was conducted with patients with PD coming to the clinic in an “off” state and receiving APL-130722 (10–30 mg). Of the 19 patients, 15 achieved a full “on” response in < 30 min, with the response lasting 50 min on average [98]. A phase III double-blind placebo-controlled trial enrolling 109 patients showed significantly greater improvements in UPDRS motor scores 30 min post-dosing with APL-130722 (primary endpoint) and a significantly greater proportion of patients achieving a full “on” state after 30 min (key secondary endpoint). Nausea, daytime somnolence and oral cavity-related adverse events (mucosal erythema, glossodynia, dry mouth, lip edema, throat irritation) were more common with active drug than with placebo [99]. A phase III open-label, randomized, crossover trial with blinded rating to evaluate APL-130277 compared with subcutaneous apomorphine in patients with PD with motor fluctuation is currently underway (ClinicalTrials.gov identifier: NCT03391882).