Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease

Mov Disord. 2014 Jan;29(1):75-82. doi: 10.1002/mds.25742. Epub 2013 Dec 13.

Abstract

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate-release carbidopa-levodopa and 3.0 hours (± 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279-carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa.

Keywords: Parkinson's disease; XP21279; dyskinesias; levodopa; motor fluctuations; pharmacokinetics.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Antiparkinson Agents / adverse effects
  • Antiparkinson Agents / pharmacokinetics
  • Antiparkinson Agents / therapeutic use*
  • Carbidopa / adverse effects
  • Carbidopa / pharmacokinetics
  • Carbidopa / therapeutic use*
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Humans
  • Levodopa / adverse effects
  • Levodopa / pharmacokinetics
  • Levodopa / therapeutic use*
  • Male
  • Middle Aged
  • Parkinson Disease / drug therapy*
  • Prodrugs / adverse effects
  • Prodrugs / pharmacokinetics
  • Prodrugs / therapeutic use*
  • Treatment Outcome

Substances

  • Antiparkinson Agents
  • Drug Combinations
  • Prodrugs
  • carbidopa, levodopa drug combination
  • Levodopa
  • Carbidopa