Disease Progression and Pharmacodynamics in Parkinson Disease – Evidence for Functional Protection with Levodopa and Other Treatments

  • Nicholas H. G. HolfordEmail author
  • Phylinda L. S. Chan
  • John G. Nutt
  • Karl Kieburtz
  • Ira Shoulson
  • Parkinson Study Group

We have modelled the Unified Parkinson’s Disease Rating Scale (UPDRS) scores collected in 800 subjects followed for 8 years. Newly diagnosed and previously untreated subjects were initially randomized to treatment with placebo, deprenyl, tocopherol or both and, when clinical disability required, received one or more dopaminergic agents (levodopa (carbidopa / levodopa), bromocriptine, or pergolide). Using models for disease progression and pharmacodynamic models for drug effects we have characterized the changes in UPDRS over time to determine the influence of the various drug treatments. We have confirmed and quantitated the relative symptomatic benefits of the dopaminergic agents and provide model-based evidence for slowing of disease progression.


levodopa deprenyl bromocriptine pergolide pharmacodynamics disease progression Parkinson’s disease 


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  1. 1.
    Fahn S. (1999). Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA. Arch. Neurol. 56(5):529–535Google Scholar
  2. 2.
    Schulzer M., Mak E., and Calne D.B. (1992). The antiparkinson efficacy of deprenyl derives from transient improvement that is likely to be symptomatic. Ann. Neurol. 32(6):795–798PubMedCrossRefGoogle Scholar
  3. 3.
    Whone A.L., Watts R.L., Stoessl A.J., Davis M., Reske S., Nahmias C. et al. (2003). Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann. Neurol. 54(1):93–101PubMedCrossRefGoogle Scholar
  4. 4.
    Parkinson Study Group. (2002). Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. J. Am. Med. Assoc. 287(13):1653–1661Google Scholar
  5. 5.
    Davis K.L., Thal L.J., Gamzu E.R., Davis C.S., Woolson R.F., Gracon S.I. et al. (1992). A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease The Tacrine Collaborative Study Group. N. Engl. J. Med. 327(18):1253–1259PubMedCrossRefGoogle Scholar
  6. 6.
    The Parkinson Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N. Engl. J. Med. 328:176–183 (1993).Google Scholar
  7. 7.
    Holford N.H.G., Ludden T. (1994). Time course of drug effect. In: Welling P.G., Balant L.P. (eds) Handbook of Experimental Pharmacology Chapter 11. Springer-Verlag, HeidelbergGoogle Scholar
  8. 8.
    Chan P.L.S. and Holford N.H.G. (2001). Drug treatment effects on disease progression. Annu. Rev. Pharmacol. Toxicol. 41:625–659PubMedCrossRefGoogle Scholar
  9. 9.
    Holford N.H.G., Kimko H.C., Monteleone J.P., and Peck C.C. (2000). Simulation of clinical trials. Annu. Rev. Pharmacol. Toxicol. 40:209–234PubMedCrossRefGoogle Scholar
  10. 10.
    The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N. Engl. J. Med. 321:1364–1371 (1989).Google Scholar
  11. 11.
    Holford N.H.G., Mould D.R., and Peck C.C. (2001). Disease Progress Models. In: Atkinson A. (eds). Principles of Clinical Pharmacology. Academic Press, San Diego, pp. 253–262Google Scholar
  12. 12.
    Holford N.H.G. and Sheiner L.B. (1981). Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin. Pharmacokinet. 6:429–453PubMedCrossRefGoogle Scholar
  13. 13.
    Holford N.H.G. and Peace K.E. (1992). Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc. Natl. Acad. Sci. USA 89:11466–11470PubMedCrossRefGoogle Scholar
  14. 14.
    Pillai G., Gieschke R., Goggin T., Jacqmin P., R.C. Schimmer, and Steimer J.L. (2004). A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis. Br. J. Clin. Pharmacol. 58(6):618–631PubMedCrossRefGoogle Scholar
  15. 15.
    Chan P.L.S., Nutt J.G., and Holford N.H.G. (2005). Pharmacokinetic and pharmacodynamic changes during the first four years of levodopa treatment in Parkinson’s disease. J. Pharmacokinet. Pharmacodyn. 32:459–484PubMedCrossRefGoogle Scholar
  16. 16.
    The Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann. Neurol. 39:37–45 (1996).Google Scholar
  17. 17.
    The Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa. Ann. Neurol. 39:29–36 (1996).Google Scholar
  18. 18.
    The Parkinson Study Group. Mortality in DATATOP: A multicenter trial in early Parkinson’s disease. Ann. Neurol. 43(3):318–325 (1998).Google Scholar
  19. 19.
    Shoulson I., Oakes D., Fahn S., Lang A., Langston J.W., LeWitt P. et al. (2002). Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann. Neurol. 51(5):604–612PubMedCrossRefGoogle Scholar
  20. 20.
    Beal S.L., Boeckmann A.J., and L. B. Sheiner. NONMEM Project Group. In. NONMEM Users Guides V. Version (ed.). University of California at San Francisco, San Francisco, 1999.Google Scholar
  21. 21.
    Sheiner L.B. (1997). Learning versus confirming in clinical drug development. Clin. Pharmacol. Ther. 61(3):275–291PubMedCrossRefGoogle Scholar
  22. 22.
    Pålhagen S., Heinonen E.H., Hägglund J., Kaugesaar T., Kontants H., Mäki-Ikola O. et al. (1998). Selegiline delays the onset of disability in de novo parkinsonian patients. Neurology 51:520–525PubMedGoogle Scholar
  23. 23.
    Holford N.H.G. (1997). Population models for Alzheimer’s and Parkinson’s disease. In: Aarons L. and Balant L.P. (eds) The Population Approach: Measuring and Managing Variability in Response, Concentration and Dose. COST B1 European Commission, Brussels, pp. 97–104Google Scholar
  24. 24.
    Contin M., Riva R., Martinelli P., Cortelli P., Albani F., and Baruzzi A. (1994). Longitudinal monitoring of the levodopa concentration-effect relationship in Parkinson’s disease. Neurology 44:1287–1292PubMedGoogle Scholar
  25. 25.
    Nutt J.G. and Holford N.H.G. (1996). The response to levodopa in Parkinson’s disease: Imposing pharmacological law and order. Ann. Neurol. 39:561–573PubMedCrossRefGoogle Scholar
  26. 26.
    Nutt J.G., Carter J.H., Lea E.S., and Sexton G.J. (2002). Evolution of the response to levodopa during the first 4 years of therapy. Ann. Neurol. 51(6):686–693PubMedCrossRefGoogle Scholar
  27. 27.
    Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch. Neurol. 61(4):561–566 (2004).Google Scholar
  28. 28.
    Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N. Engl. J. Med. 351(24):2498–2508 (2004).Google Scholar
  29. 29.
    Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease. J. Am. Med. Assoc. 284(15):1931–1938 (2000).Google Scholar
  30. 30.
    Rascol O., Brooks D.J., Korczyn A.D., De Deyn P.P., Clarke C.E., and Lang A.E. (2000). A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N. Engl. J. Med. 342(20):1484–1491PubMedCrossRefGoogle Scholar
  31. 31.
    Mallinckrodt C.H., Clark S.W., Carroll R.J., and Molenbergh G. (2003). Assessing response profiles from incomplete longitudinal clinical trial data under regulatory considerations. J. Biopharm. Stat. 13(2):179–190PubMedCrossRefGoogle Scholar
  32. 32.
    Hu C. and Sale M.E. (2003). A joint model for nonlinear longitudinal data with informative dropout. J. Pharmacokinet. Pharmacodyn. 30(1):83–103PubMedCrossRefGoogle Scholar
  33. 33.
    Muenter M.D., and Tyce G.M. (1971). L-dopa therapy of Parkinson’s disease, plasma L-dopa concentration, therapeutic response, and side effects. Mayo Clin. Proc. 46:231–239PubMedGoogle Scholar
  34. 34.
    Clarke C.E., and Davies P. (2000). Systematic review of acute levodopa and apomorphine challenge tests in the diagnosis of idiopathic Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 69(5):590–594PubMedCrossRefGoogle Scholar
  35. 35.
    Markham C.H., and Diamond S.G.(1981). Evidence to support early levodopa therapy in Parkinson disease. Neurology 31:125–131PubMedGoogle Scholar
  36. 36.
    Fahn S. (1996). Is levodopa toxic?. Neurology 47(Suppl 3):S184–S195PubMedGoogle Scholar
  37. 37.
    Murer M.G., Raisman-Vozari R. and Gershanik O. (1999). Levodopa in Parkinson’s disease: neurotoxicity issue laid to rest? Drug Saf. 21(5):339–352PubMedCrossRefGoogle Scholar
  38. 38.
    Agid Y., Chase T., and Marsden D. (1998). Adverse reactions to levodopa: drug toxicity or progression of disease?. Lancet 351(9106):851–852PubMedCrossRefGoogle Scholar
  39. 39.
    Murer M.G., Dziewczapolski G., Menalled L.B., Garcia M.C., Agid Y., Gershanik O. et al. (1998). Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Ann. Neurol. 43(5):561–575PubMedCrossRefGoogle Scholar
  40. 40.
    Olanow C.W., Hauser R.A., Gauger L., Malapira T., Koller W., Hubble J. et al. (1995). The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann. Neurol. 38:771–777PubMedCrossRefGoogle Scholar
  41. 41.
    Hauser R.A., and Holford N.H.G. (2002). Quantitative description of loss of clinical benefit following withdrawal of levodopa-carbidopa and bromocriptine in early Parkinson’s disease. Mov. Disord. 17(5):961–968PubMedCrossRefGoogle Scholar
  42. 42.
    Schapira A.H. (2003). Neuroprotection in PD-A role for dopamine agonists?. Neurology 61(6 Suppl 3):S34–42PubMedGoogle Scholar
  43. 43.
    P. Chan L.S., Nutt J.G., N. Holford H.G., and Parkinson Study Group. Application of clinical trial simulation to evaluate the ELLDOPA trial design. Mov. Disord. 17(5):S111–S112 (2002).Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Nicholas H. G. Holford
    • 1
    Email author
  • Phylinda L. S. Chan
    • 1
  • John G. Nutt
    • 2
  • Karl Kieburtz
    • 3
  • Ira Shoulson
    • 3
  • Parkinson Study Group
    • 3
  1. 1.Department of Pharmacology & Clinical PharmacologyUniversity of AucklandAucklandNew Zealand
  2. 2.Dept of NeurologyOregon Health & Science UniversityPortlandUSA
  3. 3.Dept of NeurologyParkinson Study GroupRochesterUSA

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