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Subcutaneous Levodopa/Carbidopa Combo Shows Promise for Parkinson’s Disease
Continuous, subcutaneous delivery of a high-dose levodopa/carbidopa (LD/CD) combination product (ND0612H, NeuroDerm Ltd.) may provide an effective alternative to current therapy in patients with severe Parkinson’s disease (PD), according to the results of a recent mid-stage trial.
Because of the short half-life of oral LD, patients with PD are required to take multiple LD/CD doses daily. This can result in sharp fluctuations in LD levels, which are associated with erratic “off” and “on” periods in many patients. Continuous LD administration can overcome this limitation, but steady delivery of LD is achieved only after patients have undergone a surgical procedure in which a tube is permanently implanted into the duodenum.
The primary objectives of the new phase IIa study were to assess the safety, tolerability, and pharmacokinetic characteristics of subcutaneous high- and low-dose LD/CD (ND0612H and ND0612L, respectively) in 16 patients with advanced PD and motor fluctuations who had been chronically treated with standard-of-care oral LD/CD. The patients received either ND0612H (n = 7) or ND0612L (n = 9) for 8 hours per day for 3 consecutive days, along with adjunctive oral entacapone.
An intent-to-treat analysis showed that ND0612H achieved maximum daytime LD levels of 1,333 ng/mL and 1,436 ng/mL (with different CD concentrations in the formulation), and 1,807 ng/mL with adjunctive dosing of oral entacapone. In comparison, ND0612L achieved maximum daytime LD concentrations of 528 ng/mL and 477 ng/mL (with different CD concentrations in the formulation), and 596 ng/mL with adjunctive dosing of oral entacapone, suggesting that the high-dose version (ND0612H) may provide an effective therapy alternative to current treatments requiring surgery.
Oral administration of LD/CD is regarded as the “gold standard” for patients with PD. LD crosses the blood–brain barrier and converts into dopamine to complement the reduced levels of dopamine in the brain. Virtually all patients with PD require LD at some point during treatment. However, the use of LD is limited by its short half-life. Approximately 3 to 4 hours after a single dose, almost none of the drug remains in the plasma. In addition, LD has low absorption when administered orally, with only approximately 30% of the drug entering the bloodstream.
PD is characterized by reduced dopamine in the brain, which causes trembling in the extremities and face, slowness of movement, and impaired balance and coordination. As the disease progresses, its symptoms become more severe, resulting in debilitating periods of decreased motor and non-motor functions –– referred to as the “off” time. In addition, some patients experience dyskinesia, mainly as a result of excessive or intermittent oral doses of LD aimed at treating the “off” time.
Source: NeuroDerm Ltd.; December 30, 2014.