Novel Levodopa Formulations for Parkinson’s Disease

Abstract

Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU. Levodopa-carbidopa intestinal gel (LCIG) is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube through a portable infusion pump. Ongoing studies are evaluating the 'accordion pill' (AP09004), an ER LD/CD formulation with gastroretentive properties. ND0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device, and CVT-301 is a levodopa inhalation powder with rapid onset of action; both are currently in active studies. Other novel formulations have been discontinued, including DM-1992, which is a bilayer formulation containing an IR LD/CD layer and an ER LD/CD layer with gastroretentive properties, and XP21279, a novel oral levodopa prodrug that is absorbed from the small and large intestine by high-capacity nutrient transporters expressed throughout the gastrointestinal system. ODM-101 is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg), but no active studies are underway. The current review aims to summarize the pharmacokinetic aspects, clinical efficacy, and potential adverse events of novel levodopa formulations currently available or under development.

Levodopa‐induced dyskinesia in Parkinson disease: Current and evolving concepts

“…Besides the newly approved extended‐release oral formulation of amantadine, a range of molecular and neuromodulative therapies are under evaluation in the therapeutic pipeline. It is conceivable that future improvements in L‐dopa delivery alone, through long‐acting L‐dopa preparations or infusion systems, may prevent the pharmacodynamic alterations associated with short‐acting oral L‐dopa, and thus lower the prevalence of LID if initiated early.…”

Updates and advances in the treatment of Parkinson disease

“…In order to circumvent the contribution of delayed gastric emptying to motor fluctuations, novel oral formulations or parenteral delivery of levodopa have been developed . IPX066 is an extended release formulation of levodopa–carbidopa that is marketed in the United States for treatment of motor fluctuations and reduced off time by 1.2 hours compared with immediate release treatment .…”

“…In order to circumvent the contribution of delayed gastric emptying to motor fluctuations, novel oral formulations or parenteral delivery of levodopa have been developed. 60 IPX066 is an 2 When to refer for consideration of a device-assisted therapy 38 ■ Motor fluctuations cause disability or reduced quality of life ■ Response to treatment is inconsistent ■ Dyskinesias or motor fluctuations require frequent treatment adjustment without apparent benefit ■ Levodopa required four or more times daily Narrative reviews MJA 211 (6) ▪ 16 September 2019 281 extended release formulation of levodopa-carbidopa that is marketed in the United States for treatment of motor fluctuations and reduced off time by 1.2 hours compared with immediate release treatment. 61 Inhaled levodopa 62 has been shown to be effective in improving motor function compared with placebo in fluctuators and was approved for use by the Food and Drug Administration in December 2018.…”

L‐DOPA for Parkinson's disease—a bittersweet pill

“…New formulations in clinical trials currently include inhaled (CVT‐301) (Lipp, Batycky, Moore, Leinonen, & Freed, ) for management of “OFF‐phase” and liquid for subcutaneous administration (ND0612) as a patch‐pump. ND0612 is being developed for moderate and severe disease and could produce much improved control of plasma L‐DOPA levels and therefore dyskinesia (Freitas, Ruiz‐Lopez, & Fox, ; Ramot et al., ).…”