Inhaled levodopa for intermittent treatment of OFF episodes in patients with Parkinson’s disease

ABSTRACT

Introduction: Many patients with advanced Parkinson’s disease (PD) have inadequate control of motor symptoms despite optimized treatment. Predictable and unpredictable OFF periods severely interfere with the quality of life. A drug that easily and rapidly reverts the OFF state is still needed. Subcutaneous apomorphine, the only approved drug for this indication, although efficacious, is not widely used probably due to its potential side effects and complicated administration.

Levodopa is the most efficacious drug for the treatment of PD motor symptoms. However, issues related to the oral route and intestinal absorption in later disease stages render this route lengthy and inefficacious.

Areas covered: Literature on the development of an inhaled formulation of levodopa has been reviewed. Significant advances in the field of pulmonary delivery systems and in dry powders have enabled the development of a new formulation of levodopa that can be inhaled and adequate blood levels rapidly achieved, bypassing intestinal absorption. Several clinical trials have reported efficacy, safety, and tolerability data. Some pulmonary-related adverse events have been reported but are mostly mild.

Expert opinion: This new way of administering levodopa is likely to be very welcome and may fill a gap for OFF rescue treatments, at least for some patients.

KEYWORDS:

• Levodopa
• Parkinson’s disease
• motor fluctuations
• unpredictable OFF
• rescue treatment
• apomorphine

Article highlights

• Motor fluctuations are known to affect a sizable proportion of PD patients after some years of disease and a significant number remain inadequately controlled, despite optimized treatment. The only drug approved for intermittent treatment of OFF periods is subcutaneous apomorphine.

• Inhaled levodopa (CVT-301) is a dry powder formulation of levodopa composed of 90% levodopa, 8% dipalmitoylphosphatidylcholine, and 2% sodium chloride and provided in hypromellose capsules.

• This formulation improved pharmacokinetic properties, with earlier, higher, and less variable peak plasma concentrations than with oral levodopa (time to Cmax 15 min vs. 66 min for oral administration).

• Clinical benefit was seen in 10 min and persisted for 60 min for 78% of ON responders. The average decrease in UPDRS III was 10 points. OFF time reduction in home diaries was 0.8h/day over placebo or not significant. Efficacy was not studied for early morning OFF.

• It was generally safe and well tolerated, with the most common adverse events being cough, nasopharyngitis, upper respiratory tract infections, sputum discoloration, throat irritation, rhinorrhea, nausea/dyspepsia, dyskinesia, vertigo/dizziness, and falls.

• Clinical indication is the intermittent treatment of OFF episodes in PD patients with motor fluctuations, using 84 mg (2 capsules) for each OFF episode, up to five times/day.

Declaration of interest

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.

Reviewer disclosures

A peer reviewer on this paper has disclosed that they are a consultant for Sunovion and Chiesi. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.