Profile of inhaled levodopa and its potential in the treatment of Parkinson’s disease: evidence to date

Figures & data

Table 1 Currently available levodopa formulations

Drug name and manufacturer	Drug-delivery differences from conventional IR levodopa	Potential advantages	Potential disadvantages
Sinemet (carbidopa/levodopa) MSD (Whitehouse Station, NJ, USA)	NA	NA	NA
Madopar (levodopa/benserazide) Hoffman-La Roche Ltd. (Basel, Switzerland)	NA	Fewer gastrointestinal side effects than Sinemet	NA
Sinemet CR MSD	Polymer-based controlled-release tablet	Releases ingredients over 4–6 hour period	30% less bioavailable, absorption delayed
Madopar HBS Hoffman-La Roche	Hydrodynamically balanced system that creates a gastroretentive mucous body	Releases drug at desired rate	None
Parcopa (carbidopa/levodopa) Schwarz Pharma (Mequon, WI, USA)	Rapitab technology that begins to disintegrate within seconds	Possibly shorter Tmax	None
Madopar DM Hoffman-La Roche	Disperses rapidly in a small quantity of water	Shorter Tmax and latency to “on” phases; easier to use for patients with dysphagia	None
Stalevo Novartis International AG (Basel, Switzerland)	Combination of entacapone with carbidopa/levodopa	Increases Cmax, Tmax, and AUC; allows for reduced levodopa dosing	Greater incidence and shorter time to onset of dyskinesia in early PD patients requiring levodopa therapy
Rytary (carbidopa/levodopa) Impax (Hayward, CA, USA)	Both IR and delayed-release beads of carbidopa and levodopa that dissolve at varying rates in the gastrointestinal system	Reduced time to reach 50% Cmax, longer duration that plasma levodopa concentrations remain >50%, thereby reducing “off ” time without worsening dyskinesia	Optimal dose conversion strategy not defined
Duopa/Duodopa (carbidopa/levodopa) AbbVie (Chicago, IL, USA)	Carboxymethylcellulose aqueous gel formulation of carbidopa/levodopa delivered to the proximal small intestine	Closest approximation of continuous drug delivery; pump set to deliver gel at continuous rate thereby reducing “off ” time and dyskinesia	Frequent device-related adverse events, other potential long-term complications, such as neuropathy, weight loss, impulse-control disorder

Note: Data compiled from Jimenez-Shahed,³ Steiger et al,⁴³ Dupont et al,⁴⁴ and Haglund et al.⁴⁵

Abbreviations: AUC, area under the curve; C_max, maximum plasma concentration; IR, immediate release; NA, not applicable; T_max, time to C_max.

Table 2 Novel formulations of levodopa that have been developed

Drug name and manufacturer	Differences in drug delivery from conventional carbidopa/levodopa	Potential advantages
Currently in development
APO9004 (carbidopa/levodopa) Intec Pharma (Jerusalem, Israel)	“Accordion pill” technology allows for increased gastric retention of a drug-release mechanism that consists of the active pharmaceutical ingredient loaded onto multilayered polymeric films that are folded into an accordion structure	Designed to increase the absorption phase of levodopa, leading to increased efficacy and reduced frequency of administration
ND0612, ND0612L (carbidopa/levodopa) NeuroDerm (Rehovot, Israel)	Liquid form of carbidopa and levodopa subcutaneously administered via a belt-pump or patch-pump system offering continuous parenteral administration of levodopa while avoiding unpredictable intestinal absorption and first-pass hepatic metabolism, thereby improving bioavailability of levodopa	Constant levodopa plasma concentration with decreased peak:trough ratio, reduced fluctuation index; reduced “off” time and troublesome dyskinesia
No longer in development
XP212279 XenoPort (Santa Clara, CA, USA)	Transported prodrug technology takes advantage of high-capacity nutritional transporters present throughout the gastrointestinal tract to improve absorption	Could limit problems with intestinal absorption of levodopa related to competition with dietary proteins
DM1992 Depomed (Newark, CA, USA)	Acuform technology uses swelling-polymer technology to increase gastric retention of the pharmaceutical product, which consists of a bilayer formulation of carbidopa/levodopa with an immediate-release layer and an extended-release gastroretentive core	Prolonged absorption phase of levodopa leading to more constant plasma levodopa concentration and better pharmacodynamics with reduced dose frequency
V1512/CHF1512 Chiesi Farmaceutici (Parma, Italy)	Levodopa methyl ester (melevodopa) is 250 times more soluble than levodopa, with faster onset of clinical benefit	Tendency to quicker onset of benefit, with less variability among patients

Note: Data compiled from Jimenez-Shahed.³

Jimenez-ShahedJA review of current and novel levodopa formulations for the treatment of Parkinson’s diseaseTher Deliv20167317919126893250

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SteigerMJStocchiFBramanteLRuggieriSQuinnNPThe clinical efficacy of single morning doses of levodopa methyl ester: dispersible Madopar and Sinemet plus in Parkinson diseaseClin Neuropharmacol19921565015041477849

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DupontEAndersenABoasJSustained-release Madopar HBS compared with standard Madopar in the long-term treatment of de novo parkinsonian patientsActa Neurol Scand199693114208825266

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HaglundLCrevoiserCHoogkamerJFWRelative bioavailability of the novel Madopar Dispersible tablet compared with standard MadoparFocus on Parkinson’s Disease19979710

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