Title:Levodopa in Parkinson’s Disease: Current Status and Future Developments
Volume: 16
Issue: 8
Author(s): Nicola Tambasco*, Michele Romoli and Paolo Calabresi
Affiliation:
- Clinica Neurologica, Azienda Ospedaliera-Universita di Perugia, Perugia,Italy
Keywords:
Parkinson`s disease, levodopa, pharmacology, IPX066, DM-1992, XP21279, ODM-101, LCIG.
Abstract: Background: Ever since the pioneering reports in the 60s, L-3,4-Dioxyphenylalanine
(levodopa) has represented the gold standard for the treatment of Parkinson’s Disease (PD). However,
long-term levodopa (LD) treatment is frequently associated with fluctuations in motor response
with serious impact on patient quality of life. The pharmacokinetic and pharmacodynamic
properties of LD are pivotal to such motor fluctuations: discontinuous drug delivery, short half-life,
poor bioavailability, and narrow therapeutic window are all crucial for such fluctuations. During the
last 60 years, several attempts have been made to improve LD treatment and avoid long-term complications.
Methods: Research and trials to improve the LD pharmacokinetic since 1960s are reviewed, summarizing
the progressive improvements of LD treatment.
Results: Inhibitors of peripheral amino acid decarboxylase (AADC) have been introduced to
achieve proper LD concentration in the central nervous system reducing systemic adverse events.
Inhibitors of catechol-O-methyltransferase (COMT) increased LD half-life and bioavailability. Efforts
are still being made to achieve a continuous dopaminergic stimulation, with the combination of
oral LD with an AADC inhibitor and a COMT inhibitor, or the intra-duodenal water-based LD/
carbidopa gel. Further approaches to enhance LD efficacy are focused on new non-oral administration
routes, including nasal, intra-duodenal, intrapulmonary (CVT-301) and subcutaneous (ND0612), as
well as on novel ER formulations, including IPX066, which recently concluded phase III trial.
Conclusion: New LD formulations, oral compounds as well as routes have been tested in the last
years, with two main targets: achieve continuous dopaminergic stimulation and find an instant deliver
route for LD.
