Pharmaceutical Research

, Volume 24, Issue 4, pp 791–802 | Cite as

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



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.


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.


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


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 simulation DATATOP disease progress model ELLDOPA Parkinson’s disease protective treatment 



rate of natural disease progression


symptotic maximum value of Emax


levodopa concentration in the central compartment


levodopa concentration in the peripheral compartment


levodopa concentration at which 50% of Emax is produced


levodopa concentration in the effect compartment


levodopa concentration in the slow washout compartment


total body clearance


intercompartmental clearance


natural disease progression in placebo arm


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


maximum lowering of total UPDRS that levodopa can produce


emax at time 0


effect of levodopa as an offset to the disease progress model


effect of levodopa on the slope of the disease progress model


fast washout of levodopa symptomatic benefits process


first-order absorption rate constant


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


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


probability of missing a scheduled dose having taken a dose


population parameter variability


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


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


probability of taking a scheduled dose having missed a dose


disease status at the start of the study


slow washout of levodopa symptomatic benefits process


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


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


half-life of change in Emax


equilibration half-life of the equilibration effect compartment


half-life of washout of levodopa symptomatic benefits


time of last levodopa dose


time of last observation


unified Parkinson’s Disease Rating Scale


volume of distribution of the central compartment


volume of distribution of the peripheral compartment


body weight


  1. 1.
    P. L. S. Chan and N. H. G. Holford. Drug treatment effects on disease progression. Annu. Rev. Pharmacol. Toxicol. 41:625–659 (2001).PubMedCrossRefGoogle Scholar
  2. 2.
    N. H. G. Holford, D. R. Mould, and C. C. Peck. Disease progress models. In A. Atkinson (ed.), Principles of Clinical Pharmacology, Academic, San Diego, 2001, pp. 253–262 (A. Atkinson, ed).Google Scholar
  3. 3.
    G. C. Cotzias, M. H. Van Woert, and L. M. Schiffer. Aromatic amino acids and modification of parkinsonism. N. Engl. J. Med. 276:374–379 (1967).PubMedCrossRefGoogle Scholar
  4. 4.
    M. D. Yahr, A. Wolf, J. L. Antunes, K. Miyoshi, and P. Duffy. Autopsy findings in parkinsonism following treatment with levodopa. Neurology 22:56–71 (1972).Google Scholar
  5. 5.
    S. G. Diamond, C. H. Markham, M. M. Hoehn, F. H. McDowell, and M. D. Muenter. Multi-center study of Parkinson mortality with early versus later dopa treatment. Ann. Neurol. 22:8–12 (1987).PubMedCrossRefGoogle Scholar
  6. 6.
    G. Scigliano, M. Musicco, P. Soliveri, I. Piccolo, F. Girotti, P. Giovannini, and T. Caraceni. Mortality associated with early and late levodopa therapy initiation in Parkinson’s disease. Neurology 40:265–269 (1990).PubMedCrossRefGoogle Scholar
  7. 7.
    A. H. Rajput, M. E. Fenton, S. Birdi, and R. Macaulay. Is levodopa toxic to human substantia nigra? Mov. Disord. 12:634–638 (1997).PubMedCrossRefGoogle Scholar
  8. 8.
    M. G. Murer, G. Dziewczapolski, L. B. Menalled, M. C. Garcia, Y. Agid, O. Gershanik, and R. Raisman-Vozari. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann. of Neurol. 43:561–575 (1998).CrossRefGoogle Scholar
  9. 9.
    M. A. Mena, B. Pardo, C. Paino, and J. G. De Yebenes. Levodopa toxicity in foetal rat midbrain neurones in culture: modulation by ascorbic acid. Neuroreport 4:438–440 (1993).PubMedCrossRefGoogle Scholar
  10. 10.
    C. Mytikineou, S. K. Han, and G. Cohen. Toxic and protective effects of L-dopa on mesencephalic cell cultures. J. Neurochem. 61:1470–1478 (1993).CrossRefGoogle Scholar
  11. 11.
    T. S. Smith, W. D. Parker, and J. P. Bennett. L-dopa increases nigral production of hydroxyl radicals in vivo: potential L-dopa toxicity? Neuroreport 5:1009–1011 (1994).PubMedCrossRefGoogle Scholar
  12. 12.
    I. Ziv, R. Zikha-Falb, D. Offen, A. Shirvan, and E. Melamed. Levodopa induces apoptosis in cultured neuronal cells—a possible accelerator of nigrostriatal degeneration in Parkinson’s disease? Mov. Disord. 12:17–23 (1997).PubMedCrossRefGoogle Scholar
  13. 13.
    N. H. G. Holford, P. L. S. Chan, J. G. Nutt, K. Kieburtz, I. Shoulson, and Parkinson Study Group. Disease progression and pharmacodynamics in Parkinson’s disease—evidence for functional protection with levodopa and other treatments. J. Pharmacokinet. Pharmacodyn. 33:281–311 (2006).PubMedCrossRefGoogle Scholar
  14. 14.
    The Parkinson Study Group. DATATOP: a multicenter controlled clinical trial in early Parkinson’s disease. Arch. Neurol. 46:1052–1060 (1989).Google Scholar
  15. 15.
    S. Fahn. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA [see comments]. Arch. Neurol. 56:529–535 (1999).PubMedCrossRefGoogle Scholar
  16. 16.
    S. Fahn. Earlier vs later levodopa in Parkinson disease (The ELLDOPA study), Movement Disorder Society Annual Meeting, Miami, Florida, 2002.Google Scholar
  17. 17.
    P. L. S. Chan, J. G. Nutt, and N. H. G. Holford. Application of clinical trial simulation to evaluate the ELLDOPA Trial Design, 7th International Congress of Parkinson’s Disease and Movement Disorders, Miami, Florida, United States, 2002.Google Scholar
  18. 18.
    S. Fahn, D. Oakes, I. Shoulson, K. Kieburtz, A. Rudolph, A. Lang, C. W. Olanow, C. Tanner, K. Marek, and G. Parkinson Study. Levodopa and the progression of Parkinson’s disease.[see comment]. N. Engl. J. Med. 351:2498–2508 (2004).PubMedCrossRefGoogle Scholar
  19. 19.
    P. Guimaraes, K. Kieburtz, C. G. Goetz, J. J. Elm, Y. Y. Palesch, P. Huang, B. Ravina, C. M. Tanner, and B. C. Tilley. Non-linearity of Parkinson’s disease progression: implications for sample size calculations in clinical trials. Clin. Trials 2:509–518 (2005).PubMedCrossRefGoogle Scholar
  20. 20.
    P. L. S. Chan, J. G. Nutt, and N. H. G. Holford. Importance of within subject variation in levodopa pharmacokinentics: a 4 year cohort study in Parkinson’s disease. J. Pharmacokinet. Pharmacodyn. 32:307–331 (2005).PubMedCrossRefGoogle Scholar
  21. 21.
    J. M. Cedarbaum, H. Kutt, and F. H. McDowell. A pharmacokinetic and pharmacodynamic comparison of Sinemet CR (50200) and standard Sinemet (25100). Neurology 39:38–44 (1989); discussion 59.PubMedGoogle Scholar
  22. 22.
    D. Deleu, M. Jacques, Y. Michotte, and G. Ebinger. Controlled-release carbidopalevodopa (CR) in parkinsonian patients with response fluctuations on standard levodopa treatment: clinical and pharmacokinetic observations. Neurology 39:88–92 (1989); discussion 95.PubMedGoogle Scholar
  23. 23.
    K. C. Yeh, T. F. August, D. F. Bush, K. C. Lasseter, D. G. Musson, S. Schwartz, M. E. Smith, and D. C. Titus. Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies. Neurology 39:25–38 (1989).PubMedGoogle Scholar
  24. 24.
    E. Bredberg, J. Tedroff, S. M. Aquilonius, and L. Paalzow. Pharmacokinetics and effects of levodopa in advanced Parkinson’s disease. Eur. J. Clin. Pharmacol. 39:385–389 (1990).PubMedCrossRefGoogle Scholar
  25. 25.
    S. Harder and H. Baas. Concentration-response relationship of levodopa in patients with different stages of Parkinson’s disease. Clin. Pharmacol. Ther. 64:183–191 (1998).PubMedCrossRefGoogle Scholar
  26. 26.
    N. H. G. Holford. A size standard for pharmacokinetics. Clin. Pharmacokinet. 30:329–332 (1996).PubMedGoogle Scholar
  27. 27.
    N. H. G. Holford and L. B. Sheiner. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokinet. 6:429–453 (1981).PubMedCrossRefGoogle Scholar
  28. 28.
    P. L. S. Chan, J. G. Nutt, and N. H. G. Holford. Pharmacokinetic and pharmacodynamic changes over 4 years of levodopa treatment in patients with Parkinson’s disease. J. Pharmacokinet. Pharmacodyn. 32:459–484 (2005).PubMedCrossRefGoogle Scholar
  29. 29.
    R. A. Hauser and N. H. G. Holford. Quantitative description of loss of clinical benefit following withdrawal of levodopa-carbidopa and bromocriptine in early Parkinson’s disease. Mov. Disord. 17:961–968 (2002).PubMedCrossRefGoogle Scholar
  30. 30.
    J. G. Nutt, J. H. Carter, E. S. Lea, and G. J. Sexton. Evolution of the response to levodopa during the first 4 years of therapy. Ann. Neurol. 51:686–693 (2002).PubMedCrossRefGoogle Scholar
  31. 31.
    Pharsight Corporation. Pharsight Trial Simulator User’s Guide, Pharsight, California, 2002.Google Scholar
  32. 32.
    S. L. Beal, A. J. Boeckmann, and L. B. Sheiner. NONMEM Project Group. NONMEM Users Guides, University of California at San Francisco, San Francisco, 1999.Google Scholar
  33. 33.
    R. A. Hauser, W. C. Koller, J. P. Hubble, T. Malapira, K. Busenbark, and C. W. Olanow. Time course of loss of clinical benefit following withdrawal of levodopacarbidopa and bromocriptine in early Parkinson’s disease. Mov. Disord. 15:485–489 (2000).PubMedCrossRefGoogle Scholar

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

Personalised recommendations