Pharmacokinetic and Pharmacodynamic Changes During the First Four Years of Levodopa Treatment in Parkinson’s Disease

  • Phylinda L. S. Chan
  • John G. Nutt
  • Nicholas H. G. Holford
Article

Abstract

The purpose of this analysis is to describe how levodopa pharmacokinetic and pharmacodynamic parameters change over the first 4 years of long-term levodopa treatment in patients with Parkinson’s disease. Twenty previously untreated Parkinsonian patients were admitted to the general clinical research center (GCRC) for 4 days at the beginning of long-term levodopa therapy and 6, 12, 24 and 48 months later. On each GCRC admission, patients received a 2 hr IV infusion of levodopa on day 1 and day 4 with no oral levodopa between the infusions. After the first GCRC admission patients were treated with oral levodopa dosed for optimal control of Parkinsonism. Motor function was measured by finger tapping rate. A pharmacokinetic–pharmacodynamic model incorporating 3 effect compartments was used to fit the individual plasma levodopa concentrations and tapping rates. Motor function before the first levodopa infusion (E01) improved over the first 20 months and subsequently returned to the initial baseline at the start of the study. A similar pattern was seen in motor function before the second infusion (E02) after the 3 days levodopa withdrawal, with a decline predicted to fall below the initial baseline at the start of the study by 6 years. Eight patients showed an increase in maximum tapping rate with levodopa (Emax) approaching a steady state after 16 months. Ten patients showed an increase in Emax with a peak at 31 months. One patient showed a linear decrease and another patient did not change over the 48 months. Longitudinal progress models were used to describe the time course of pharmacokinetic and pharmacodynamic parameters over 4 years. Peak treatment benefit, defined as the difference between Emax and E01 or E02 (Dmax1 or Dmax2), increased with time particularly after the 3-day levodopa withdrawal. Deterioration of pre-dose motor function (E0) as disease progresses coupled with a greater amplitude of response due to levodopa (Dmax) could be a key factor contributing to motor fluctuations associated with long-term levodopa treatment.

Keywords

levodopa pharmacokinetics pharmacodynamics disease progression Parkinson’s disease fluctuations 

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Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Phylinda L. S. Chan
    • 1
    • 3
  • John G. Nutt
    • 2
  • Nicholas H. G. Holford
    • 1
  1. 1.Department of Pharmacology and Clinical PharmacologyUniversity of AucklandAucklandNew Zealand
  2. 2.Department of Neurology and Physiology & PharmacologyPortland VA Medical Center and Oregon Health Sciences UniversityPortlandUSA
  3. 3.Pfizer IncMichiganUSA

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