Levodopa slows progression of Parkinson's disease: external validation by clinical trial simulation

Pharm Res. 2007 Apr;24(4):791-802. doi: 10.1007/s11095-006-9202-3. Epub 2007 Feb 17.

Abstract

Purpose: To externally validate the model predictions of a DATATOP cohort analysis through application of clinical trial simulation with the study design of the ELLDOPA trial.

Methods: The stochastic pharmacokinetic-pharmacodynamic and disease progress model was developed from the large DATATOP cohort of patients followed for 8 years. ELLDOPA was designed to detect a difference between placebo and levodopa treated arms in the total Unified Parkinson's Disease Rating Scale (UPDRS) taken at baseline and following 2 weeks levodopa washout after 40 weeks of treatment. The total UPDRS response was simulated with different assumptions on levodopa effect (symptomatic with/without disease modifying capability) and washout speed of symptomatic effect.

Results: The observed results of ELLDOPA were similar to the model predictions assuming levodopa slows disease progression and has a slow washout of symptomatic effect.

Conclusions: This simulation work confirmed the conclusion of the DATATOP analysis finding that levodopa slows disease progression. The simulation results also showed that a dose-related increased rate of progression in Parkinson's disease, obscured by symptomatic benefit, is very unlikely. Finally, the simulation results also shown that 2 weeks washout period was not adequate to completely eliminate the symptomatic benefits of levodopa.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Validation Study

MeSH terms

  • Antiparkinson Agents / adverse effects
  • Antiparkinson Agents / pharmacokinetics
  • Antiparkinson Agents / therapeutic use*
  • Cohort Studies
  • Computer Simulation*
  • Disease Progression
  • Follow-Up Studies
  • Humans
  • Levodopa / adverse effects
  • Levodopa / pharmacokinetics
  • Levodopa / therapeutic use*
  • Models, Biological*
  • Parkinson Disease / drug therapy*
  • Predictive Value of Tests
  • Reproducibility of Results
  • Research Design*
  • Time Factors
  • Treatment Outcome

Substances

  • Antiparkinson Agents
  • Levodopa