Istradefylline – a first generation adenosine A_2A antagonist for the treatment of Parkinson’s disease

ABSTRACT

Introduction It is now accepted that Parkinson’s disease (PD) is not simply due to dopaminergic dysfunction, and there is interest in developing non-dopaminergic approaches to disease management. Adenosine A_2A receptor antagonists represent a new way forward in the symptomatic treatment of PD.

Areas covered In this narrative review, we summarize the literature supporting the utility of adenosine A_2A antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A_2A antagonist currently in clinical use.

Expert opinion: At this time, the use of istradefylline in the treatment of PD is limited to the management of motor fluctuations as supported by the results of randomized clinical trials and evaluation by Japanese and USA regulatory authorities. The relatively complicated clinical development of istradefylline was based on classically designed studies conducted in PD patients with motor fluctuations on an optimized regimen of levodopa plus adjunctive dopaminergic medications. In animal models, there is consensus that a more robust effect of istradefylline in improving motor function is produced when combined with low or threshold doses of levodopa rather than with high doses that produce maximal dopaminergic improvement. Exploration of istradefylline as a ‘levodopa sparing’ strategy in earlier PD would seem warranted.

KEYWORDS:

• Adenosine
• a_2a receptors
• istradefylline
• motor fluctuations
• off time
• parkinson’s disease
• treatment

Article highlights

• The translation of laboratory experience, based on the emerging understanding of motor pathways downstream from the striatum, led to the development of selective adenosine A_2A receptor antagonists for advanced Parkinson disease

• Istradefylline has high selectivity for blocking the adenosine A_2A receptor and exerts virtually no clinically relevant off-target neurochemical effects

• The istradefylline clinical trial development program focused on lessening OFF time when used as an adjunct to levodopa with or without other anti-parkinsonian drugs.

• Based on multiple clinical trials, istradefylline has been approved for marketing in Japan and the USA for the management of motor fluctuations (‘wearing-off’ and ‘OFF episodes’, respectively).

Acknowledgments

The authors thank Tomoyuki Kanda and Mayumi Saki (Kyowa Kirin) for their assistance with the literature review as well as Anita Chadha-Patel and Elizabeth Hocking of ACP Clinical Communications Ltd (funded by Kyowa Kirin Inc.) for medical writing support (literature searching, referencing and editing) in the development of this report.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

Peter Jenner has received honoraria for consultancy and advisory boards from Kyowa Kirin Co. Akihisa Mori is employed by Kyowa Kirin Co., Ltd. Robert A Hauser reports consultancy/advisory boards for Kyowa Kirin Pharmaceuticals and has been a principal investigator in clinical trials of istradefylline. Stephen Aradi has nothing to report in relation to this work. No author has received specific remuneration for this work.

Additional information

Funding

This paper was supported by Kyowa Kirin, Inc. who procured medical writing support. No author received any remuneration for the preparation of this article.