Inhaled Apomorphine as a Rescue Treatment in Parkinson's Disease
Abstract & Commentary
By Alexander Shtilbans, MD, PhD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Shtilbans reports no financial relationships relevant to this field of study.
Synopsis: Inhaled apomorphine, at doses up to 0.8 mg, appears safe and well tolerated by patients with Parkinson's disease, but does not result in significant improvement in wearing "off" periods, at the tested doses.
Source: Grosset KA, et al. Phase IIa randomized double-blind, placebo-controlled study of inhaled apomorphine as acute challenge for rescuing "off" periods in patients with established Parkinson's disease. Eur J Neurol 2013;20:1445-1450.
Parkinson's disease causes severe motor symptoms — rigidity, bradykinesia, resting tremor, and postural instability. The motor symptoms respond to dopaminergic therapies such as dopamine agonists or levodopa. However, after several years of treatment, some patients develop motor fluctuations, such as dyskinesias and wearing "off" episodes. Young patients and those taking high doses of levodopa are more prone to developing dyskinesias. Wearing "off" is a troubling symptom that occurs at the end of the active period of a levodopa dose, and in some cases at any time. Presently, there are no safe and effective non-parenteral, FDA-approved, rapid-acting treatments to modify these episodes. Apomorphine, a potent dopamine agonist, has been studied as a rescue medication for wearing "off" episodes. When injected subcutaneously, however, it may cause severe nausea, vomiting, and skin reactions. Therefore, alternative routes of administration are being sought.
The authors of this paper conducted a single-center, randomized, double-blind, placebo-controlled study of the inhaled formulation of apomorphine for rescue treatment during "off" periods in patients with Parkinson's disease. The study aimed to find the minimum efficacious dose of inhaled apomorphine, as well as evaluate the safety, tolerability, and pharmacokinetics of this drug. Three different doses of apomorphine were compared to placebo. Parkinson's disease subjects had the disease for at least 3 years, complicated by motor fluctuations, and were in Hoehn and Yahr stage 2 to 2.5. Three dosage arms tested inhaled apomorphine doses of 0.2 mg, 0.5 mg, and 0.8 mg. Each arm included six patients receiving the drug and two receiving placebo. The primary endpoint was the proportion of patients who reported being in an "on" state at any time after dosing, and the time to improvement from "off" to "on." The secondary endpoint was the duration of the "on" state after dosing. Other outcomes measured were the change in the UPDRS 3 upper limb score, before and after dosing. Demographic characteristics of the patients within the three groups were comparable, except for the group receiving 0.8 mg of apomorphine, who were all males. The proportion of patients in the "on" state after receiving the drug was 0% at 0.2 mg, 50% at 0.5 mg, and 33.3% at 0.8 mg. One-sixth (16.7%) of patients receiving placebo achieved the "on" state (P = 0.1311). The mean duration of "on" time after dosing was 10 minutes for the 0.2 mg dose, and 40 minutes for 0.5 mg and 0.8 mg of apomorphine. Placebo was associated with 20 minute-mean duration of "on" time. The changes in UPDRS 3 were not significantly different between the active drug groups and placebo. Dyskinesias were not observed. Inhaled apomorphine was rapidly absorbed, achieving peak blood concentration at 1-3 minutes. The most common side effects for apomorphine and the placebo groups were headache and paresthesias.
The authors concluded that the inhaled formulation of apomorphine, at the doses studied, was well tolerated, but the small sample size limited the interpretation of the efficacy data of the study, which was not significantly different from placebo.
Commentary
This is the first trial that evaluated the inhaled formulation of apomorphine and showed that it has high bioavailability, making it a potentially good rescue medication. However, the number of trial subjects was small and the group of patients receiving the highest dose of the drug was entirely male. There was a suggestion of efficacy at the highest dose of apomorphine tested (0.8 mg), but this was not significantly different from the placebo effects. Therefore, it will be important to test the drug in a larger group that includes women. The authors enrolled patients with a Hoehn and Yahr score of 2 to 2.5, which represents a moderate stage of disease, and would exclude some patients with more severe motor complications, including "off" periods. Only upper limbs were evaluated, limiting the assessment of patients with lower body-predominant Parkinson's disease.
The lack of significant adverse events or serious side
effects, including nausea and vomiting, is encouraging and warrants further studies of inhaled apomorphine at
higher doses and in a larger and more diverse group of patients.
