Inhaled Parkinson Disease Drug May Signal New Era of Alternative Treatment Options

A new inhaled product for patients with Parkinson Disease (PD) will be available soon by prescription. Approved by the FDA on December 21, 2018,1 this product is unique in that it is an inhaled medication that is not for the treatment of an acute or chronic disease affecting the lungs. 

Levodopa inhalation powder (Inbrija, Acorda Therapeutics) is a novel form of levodopa, the traditional staple in PD treatment. Levodopa has been available orally for decades, but currently is only available in a combination product with carbidopa. The combined effect of relatively low bioavailability and the impact of food on absorption can allow blood concentrations of the drug to fluctuate, with time patient response to levodopa decline.2-4 This can lead to off episodes, in which symptoms are much less controlled.2 It is estimated that 40% of patients with PD will experience off episodes after 4 to 6 years of levodopa therapy and up to 70% will within 9 years.3

Levodopa inhalation powder is approved for patients who are already on carbidopa/levodopa and intended to be administered during off periods.5 Two capsules (42 mg each or 84 mg per dose) can be inhaled up to 5 times per day (maximum daily dose is 420 mg). The inhaled medication is absorbed through the epithelium of alveoli capillaries quickly into the blood.
 
It is not recommended for patients with chronic pulmonary disease, those with a history of hallucinations or psychosis, and those currently taking or within 2 weeks of stopping a nonselective monoamine oxidase inhibitor. Although reported adverse effects were generally mild (cough, nausea, upper respiratory tract infection), inhaled levodopa must be obtained through a specialty pharmacy.3,5

The dry powder inhaler with levodopa has been in development for several years. Animal studies indicated that pulmonary delivery of the medication resulted in faster serum levels and higher peak concentrations versus comparable oral doses.2 Pulmonary delivery is proposed to result in better, more predictable absorption.6
 
Although the use of the inhaler system may appear cumbersome for a patient with PD motor symptoms, studies have shown that most patients found it easy to use.3 Just as is the case with inhaled drugs for pulmonary diseases, the breath-activated system may prove to be beneficial in age-related decreases in lung compliance and the effect of disease progression on the patient's ability to deeply inhale.

A small study of 75 patients (mean age 62 years) showed significant improvement in motor function compared with placebo when administered during off periods. Onset of the agent was seen within 10 minutes, clinical effects were still present at the 60 minute assessment, and higher doses resulted in longer durations of action. Patients were able to navigate the 2-dose system at a mean of 1.5 minutes.

Another article summarizing a pair of phase 2 studies demonstrated the safety of inhaled levodopa and a lack of impact on pulmonary function.4 A 12-week placebo-controlled phase 3 trial showed significant improvements in motor function within 10 minutes that persisted for an hour after the dose, an effect that lasted for the duration of the study. 6
 
However, there were no significant differences compared with placebo in off time experienced by the patient (as reported in patient diaries). It is important to note that all of the studies evaluated inhaled levodopa as add-on therapy to traditional chronic therapy.
 
To date, there are no published data supporting the concept of using the inhaled product as maintenance therapy. Since pricing is unclear at this time, and as pharmacoeconomic studies have not been conducted, it remains to be seen what the full impact of inhaled levodopa will have on PD therapy.

The advent of inhaled medications for conditions unrelated to the pulmonary system is an interesting advancement in pharmacy and medicine. It opens the doorway for redevelopment of medications that can be beneficial to treat numerous disease states and conditions but are limited by poor or erratic bioavailability.
 
Only time will tell if the inhalation route will become a popular and common alternative to the oral route of administration, but with the approval of inhaled levodopa, it has been shown that the concept can be done.

References
  1. Acorda Therapeutics Announces FDA Approval of INBRIJA™ (levodopa inhalation powder). Associated Press. https://apnews.com/1f03015a35954404ac15ba0f215b853e. Published December 21, 2018. Accessed January 22, 2019.
  2. Muinstra M, Grasmeijer F, Hagedoorn P, et al. European Journal of Pharmaceutics and Biopharmaceutics.2015;97:22-29
  3. LeWitt PA, Hauser RA, Grosset DG et al. Mov Disord.2016;31:1356-1365
  4. LeWitt PA, Pahwa R, Sedkov A, et al. Pulmonary safety and tolerability of inhaled levodopa (CVT-301) administered to patients with Parkinson’s Disease. J Aerosol Med Pulm Drug Deliv. 2018;31:155-161
  5. Prescribing Information. Inbrija (Levodopa Inhalation). Acordia Therapeutics, Inc.2018. Ardsley, New York
  6. Patel AB, Kimenez-Shahed J. Profile of inhaled levodopa and its potential in the treatment of Parkinson’s disease: evidence to date. Neuropsychiatr Dis. Treat.2018;14:2955-2964
 



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