Importance of Within Subject Variation in Levodopa Pharmacokinetics: A 4Year Cohort Study in Parkinson’s Disease

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

Abstract

The purpose of the study was to describe the population pharmacokinetics of levodopa in patients with Parkinson’s disease studied in 5 trials (10 occasions) over 4 years. Twenty previously untreated Parkinsonian patients were investigated. Each trial consisted of a 2-hr IV infusion of levodopa (1 mg/kg/h) with concomitant oral carbidopa given on two occasions separated by 72hr with no levodopa in between. This trial design was repeated at 6, 12, 24 and 48 months. A two-compartment pharmacokinetic model with central volume (V1), peripheral volume (V2), clearance (CL) and inter-compartmental clearance (CLic) was used to fit plasma levodopa concentrations. The model accounted for levodopa dosing prior to each trial and endogenous levodopa synthesis. Population parameter estimates (geometric mean) and population parameter variability (PPV; SD of normal distribution) were V1 11.4 l/70 kg (0.44), CL 30.9 l/h/70 kg (0.25), V2 27.3 l/70 kg (0.27), and CLic 34.6 l/h/70 kg (0.48). PPV was partitioned into between subject variability (BSV) which was 0.12 V1, 0.13 CL, 0.15 V2, 0.28 CLic, within trial variability (WTV) which was 0.16 V1, 0.13 CL, 0.08 V2, 0.18 CLic and between trial variability (BTV) which was 0.40 V1, 0.17 CL, 0.21 V2, 0.34 CLic. Neither structural nor random levodopa pharmacokinetic parameters were associated with the time course of development of fluctuation in motor response. Variability in levodopa pharmacokinetic parameters (particularly V1) may result in variability in plasma levodopa concentrations that could contribute to fluctuations in motor response.

Keywords

levodopa within subject variability pharmacokinetics Parkinson’s disease population approach 

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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, Physiology and PharmacologyPortland VA Medical Center and Oregon Health Sciences UniversityPortlandUSA
  3. 3.Pfizer Inc.Ann ArborMichiganUSA

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