Clinical trial simulation: disease progression and treatment modifications in Parkinson’s Disease
Abstract (Summary)Clinical trial simulation (CTS) and modelling are techniques which play an important role in clinical pharmacology and drug development. The goal of this thesis is to apply techniques in CTS and modelling for studying disease progression and the pharmacokinetics and pharmacodynamics of levodopa in Parkinson's disease. Three components of levodopa response can be identified in patients with Parkinson's disease; a transient short-duration response, a sustained long-duration response to exogenous levodopa, and diurnally varying endogenous levodopa synthesis. A pharmacokinetic-pharmacodynamic model was developed to describe the individual components of levodopa response. Twenty-one previously untreated (de novo) patients with Parkinson's disease and 12 patients who had received levodopa orally for 9.7 ± 4.0 years were investigated. Twenty de novo patients were examined at 6, 12, 24 and 48 months. No systematic changes in levodopa pharmacokinetics were found in the first 4 years of long-term levodopa treatment. A lowered baseline motor response and an increase in efficacy with time result in an exaggerated short-duration response which might be key contributors to the development of motor fluctuations with long-term levodopa treatment. The capability of CTS to generate typical responses was evaluated. If progression rate of bradykinesia is influenced by age then it should be possible to detect this effect using reasonable clinical trial designs. The ELLDOPA trial aims to determine if levodopa slows or accelerates the rate of disease progression of Parkinson's disease. The power of the ELLDOPA trial design was evaluated using a clinical pharmacology model. The simulation results suggested that the short washout period for levodopa symptomatic effect could lead to a false conclusion about the nature of the levodopa treatment effect. This thesis has shown that pharmacodynamic or disease progression factors rather than pharmacokinetic changes are responsible for the development of motor fluctuations in Parkinson's disease. It has quantified the unexpected development of increased efficacy of levodopa over time. Clinical trials designed to evaluate disease progression without recognising washout of the long-duration response of levodopa can lead to misinterpretation of trial outcomes. However, model based approaches can disentangle these confounding factors and dissect the underlying effects of drug action on disease progression.
School Location:New Zealand
Source Type:Master's Thesis
Date of Publication:01/01/2004