Novel levodopa formulations in the treatment of Parkinson's disease

Abstract

Levodopa is the gold standard in Parkinson's disease (PD) treatment but its use is associated with motor complications. Levodopa pharmacokinetics, a short half-life, erratic gastric emptying and duodenal absorption, are key factors in their pathogenesis. As the disease progresses, frequency of levodopa administrations is increased leading to a complex treatment schedule and poor patient compliance. The development of long acting formulations ensuring continuous delivery is therefore crucial to improve daily motor control. Available controlled release levodopa formulations produce more sustained plasma levels but also show lower bioavailability and slower time to peak, resulting in poor clinical outcome especially in advanced patients. IPX066 is a newly developed experimental formulation with a more favorable plasma profile than immediate-release levodopa, resulting in improved motor control and reduced dose frequency, which may increase adherence. Novel delivery systems such as inhaled levodopa or transdermal levodopa micropumps are also currently being investigated for efficacy with promising future perspectives.

Keywords::

• COMT
• duodenal infusion
• dyskinesia
• IPX066
• levodopa
• MAO-B inhibitor
• motor complications
• Parkinson's disease
• pharmacokinetic
• wearing-off

Financial & competing interests disclosure

A Antonini has received honoraria for consulting services and symposia from AbbVie, Boheringer Ingelheim, GSK, Lundbeck, UCB, Novartis and Merck Serono. 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Levodopa (LD) pharmacokinetics, short half-life, erratic gastric emptying and duodenal absorption are the main factors which lead to motor complications in Parkinson's disease (PD).

• Pulsatile dopaminergic stimulation not only results in unsteady control of motor symptoms, but also contributes to the onset of dyskinesias.

• Available oral strategies, such as adding catechol-O-methyl transferase and monoamine oxidase inhibitors, improve LD plasma profile and motor fluctuations, but are not sufficient to obtain a steady motor control through all the day.

• Continuous delivery of dopaminergic drugs through subcutaneous infusion of apomorphine or intraduodenal LD reduces motor complications in advanced PD.

• IPX066 is an oral, extended-release capsule formulation of carbidopa/levodopa, developed to ensure more stable than immediate-release LD plasma levels and to improve motor control of PD.

• Transnasal and sublingual administration has been developed for different dopaminergic compounds and for LD itself, but this route may only be suitable for intermittent and not prolonged delivery.