Can Levodopa Delivery Be Improved: No

Levodopa with carbidopa is undoubtedly the gold standard of treatment for Parkinson's disease. But an initial spectacular benefit with this drug, known as the honeymoon period, is often compromised within a few years by the occurrence of disabling fluctuations and dyskinesia. The reasons for this switch are poorly understood, but probably involve pharmacokinetic factors, including the erratic absorption and short elimination half-life of levodopa combined with pharmacodynamic post-synaptic changes, resulting from the abnormal pulsatile stimulation of the system by the drug. Several attempts in the past with purported controlled-release formulations of levodopa proved disappointing. In the recent years though, new extended release formulations, and novel delivery strategies (nanoparticles, transdermal, nasal, etc.) have been developed and some of them tested in patients, reigniting the hope for successful improved levodopa delivery. LD methylester (ME) is a highly soluble prodrug that provides a more rapid and consistent absorption and therefore, more rapid onset of action versus standard oral LD preparations, while the half-life of the two preparations is similar. In a randomized trial, comparing the effectiveness of methylester with standard LD in 221 patients with advanced PD, the total daily off-time between the two groups was not statistically significant 1. IPX066, is a new oral extended-release formulation of carbidopa-levodopa, which has already completed two randomized phase III clinical trials. In the first study, applying a complicated double-blind randomized switch design in 393 patients, Hauser et al., showed that IPX066 reduced off-time by approximately 1 h per day compared with standard immediate-release carbidopa/levodopa 2. Certain methodological issues relating to the long and complex process to switch patients from immediate-release carbidopa-levodopa to IPX066, are of concern. In addition, patients still endured nearly 4 h of off-time after switching to IPX066, which can still greatly affect everyday life of patients. Indeed the described benefit was not reflected in the quality of life ratings. The second, recently published, is a smaller double-blind, randomized study of IPX066 in patients with fluctuating PD. The study used a crossover design with two double-blind 2-week periods interrupted by a 1-week open-label wash-out period, during which all patients were treated with IPX066 3. During double-blind treatment, there was a statistically significant difference, with 8.5% less OFF time on IPX066 versus LCE. Again the benefit was not reflected in quality of life ratings. A new combination of fixed doses of carbidopa, regardless of L-dopa dose strength, has been tested in a proof-of-concept phase …