Pharmaceutical Research

, Volume 24, Issue 4, pp 791–802

Levodopa Slows Progression of Parkinson’s Disease. External Validation by Clinical Trial Simulation

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

DOI: 10.1007/s11095-006-9202-3

Cite this article as:
Chan, P.L.S., Nutt, J.G. & Holford, N.H.G. Pharm Res (2007) 24: 791. doi:10.1007/s11095-006-9202-3
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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.

Key words

clinical trial simulationDATATOPdisease progress modelELLDOPAParkinson’s diseaseprotective treatment

Abbreviations

α

rate of natural disease progression

BEML

symptotic maximum value of Emax

C1

levodopa concentration in the central compartment

C2

levodopa concentration in the peripheral compartment

C5L

levodopa concentration at which 50% of Emax is produced

Ce

levodopa concentration in the effect compartment

CeSlow

levodopa concentration in the slow washout compartment

CL

total body clearance

CLic

intercompartmental clearance

DprogPCB

natural disease progression in placebo arm

ED50

levodopa concentration (relative to a 300 mg/d dose rate) at which 50% of Emax is produced

Emax

maximum lowering of total UPDRS that levodopa can produce

Emax0

emax at time 0

EO

effect of levodopa as an offset to the disease progress model

ES

effect of levodopa on the slope of the disease progress model

FWO

fast washout of levodopa symptomatic benefits process

KA

first-order absorption rate constant

KLDP

protective effect parameter for the rate of disease progression in relation to levodopa concentration

KLDT

toxic effect parameter for the rate of disease progression in relation to levodopa concentration

Pmiss

probability of missing a scheduled dose having taken a dose

PPV

population parameter variability

Prot_Symp_SWODOSE

simulated total UPDRS in a specific dose arm assuming levodopa has both functional protective and symptomatic benefits and with a slow washout process for the symptomatic benefit after levodopa withdrawal

ProtDFP

size of protective effect (%) computed using the difference from placebo approach

Ptake

probability of taking a scheduled dose having missed a dose

S0

disease status at the start of the study

SWO

slow washout of levodopa symptomatic benefits process

Symp_SWODOSE

simulated total UPDRS in a specific dose arm assuming levodopa only has symptomatic benefit and with a slow washout process

SympDFP

size of symptomatic effect (%) computed using the difference from placebo approach

TEML

half-life of change in Emax

TEQL

equilibration half-life of the equilibration effect compartment

TEQWO

half-life of washout of levodopa symptomatic benefits

Tlastdose

time of last levodopa dose

Tlastobs

time of last observation

UPDRS

unified Parkinson’s Disease Rating Scale

V1

volume of distribution of the central compartment

V2

volume of distribution of the peripheral compartment

WT

body weight

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Phylinda L. S. Chan
    • 1
  • John G. Nutt
    • 2
  • Nicholas H. G. Holford
    • 1
    • 3
  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.Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health SciencesThe University of AucklandAucklandNew Zealand