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Modeling the Short- and Long-Duration Responses to Exogenous Levodopa and to Endogenous Levodopa Production in Parkinson's Disease

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

Abstract

Clinicians recognize levodopa has a short-duration response (measured in hr) and a long-duration response (measured in days) in Parkinson's disease. In addition there is a diurnal pattern of motor function with better function in the morning. Previous pharmacokinetic-pharmacodynamic modeling has quantified only the short-duration response. We have developed a pharmacokinetic-pharmacodynamic model for the short- and long-duration responses to exogenous levodopa and the effects of residual endogenous levodopa synthesis in patients with Parkinson's disease. Thirteen previously untreated (de novo) patients with Parkinson's disease and twelve patients who had received levodopa orally for 9.7 ± 4.0 years (chronic) were investigated. A 2 hr IV infusion of levodopa with concomitant oral carbidopa was given on two occasions separated by 3 days with no levodopa in between. A two compartment pharmacokinetic model was used to fit plasma levodopa concentrations. A sigmoid Emax model was used to relate concentrations from endogenous and exogenous sources to tapping rate (a measure of motor response). A model incorporating three effect compartments (fast equilibration (half life, Teqf), slow equilibration (Teqs) and dopa synthesis (Teqd)), yielded the most descriptive model for levodopa pharmacokinetics and pharmacodynamics. Baseline tapping rate reflected endogenous levodopa synthesis and the long-duration response. Partial loss of the long-duration response during the 3 days without levodopa in the chronic group lowered baseline tapping (36 ± 7%, mean ± SEM) and increased maximum levodopa induced response above baseline (112 ± 31%). The maximum levodopa induced response after the drug holiday is a result of lowered baseline tapping due to the loss of long-duration response and not due to a change in levodopa pharmacokinetics or pharmacodynamics.

pharmacokinetics pharmacodynamics levodopa Parkinson's disease long-duration response 

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REFERENCES

  1. 1.
    M. V. Nelson, R. C. Berchou, P. A. Lewitt, D. Kareti, N. Kesaree, P. Schlick, and M. P. Galloway. Pharmacokinetic and pharmacodynamic modeling of L-dopa plasma concentrations and clinical effects in Parkinson's disease after Sinemet. Clin. Neuropharmacol. 12:91–97 (1989).PubMedGoogle Scholar
  2. 2.
    M. Contin, R. Riva, P. Martinelli, and A. Baruzzi. Pharmacodynamic modeling of oral levodopa: clinical application in Parkinson's disease. Neurology 43:367–371 (1993).PubMedGoogle Scholar
  3. 3.
    S. Harder, H. Baas, N. Bergemann, L. Demisch, and S. Rietbrock. Concentration-effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation. Br. J. Clin. Pharmacol. 39:39–44 (1995).PubMedGoogle Scholar
  4. 4.
    M. D. Muenter and G. M. Tyce. L-dopa therapy of Parkinson's disease, plasma L-dopa concentration, therapeutic response, and side effects. Mayo Clin. Proc. 46:231–239 (1971).PubMedGoogle Scholar
  5. 5.
    C. L. Comella, J. Bohmer, and G. T. Stebbins. Sleep benefit in Parkinson's disease (Abstract). Mov. Disord. 45:A286 (1995).Google Scholar
  6. 6.
    L. J. Currie, J. P. Bennett, Jr., M. B. Harrison, J. M. Trugman, and G. F. Wooten. Clinical correlates of sleep benefit in Parkinson's disease. Neurology 48:1115–1117 (1997).PubMedGoogle Scholar
  7. 7.
    M. Merello, A. Hughes, C. Colosimo, M. Hoffman, S. Starkstein, and R. Leiguarda. Sleep benefit in Parkinson's disease. Movement Disorders 12:506–508 (1997).PubMedGoogle Scholar
  8. 8.
    J. G. Nutt, J. H. Carter, and W. R. Woodward. Long-duration response to levodopa. Neurology 45:1613–1616 (1995).PubMedGoogle Scholar
  9. 9.
    J. G. Nutt, J. H. Carter, L. Van Houten, and W. R. Woodward. Short-and longduration responses to levodopa during the first year of levodopa therapy. Ann. Neurol. 42:349–355 (1997).PubMedGoogle Scholar
  10. 10.
    D. E. Bateman, K. Levett, and C. D. Marsden. Sleep benefit in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 67:384–385 (1999).PubMedGoogle Scholar
  11. 11.
    J. G. Nutt, W. R. Woodward, J. H. Carter, and S. T. Gancher. Effect of long-term therapy on the pharmacodynamics of levodopa. Relation to On-Off phenomenon. Arch. Neurol. 49:1123–1130 (1992).PubMedGoogle Scholar
  12. 12.
    J. G. Nutt, J. H. Carter, and W. R. Woodward. Effect of brief levodopa holidays on the short-duration response to levodopa. Evidence for tolerance to the antiparkinsonian effects. Neurology 44:1617–1622 (1994).PubMedGoogle Scholar
  13. 13.
    W. R. Gibb and A. J. Lees. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 51:745–752 (1988).PubMedGoogle Scholar
  14. 14.
    A. J. Hughes, Y. Ben-Shlomo, S. E. Daniel, and A. J. Lees. What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology 42:1142–1146 (1992).PubMedGoogle Scholar
  15. 15.
    D. J. Gelb, E. Oliver, and S. Gilman. Diagnostic criteria for Parkinson disease. Arch. Neurol. 56:33–39 (1999).CrossRefPubMedGoogle Scholar
  16. 16.
    J. G. Nutt, W. R. Woodward, J. P. Hammerstad, J. H. Carter, and J. L. Anderson. The ''On-Off'' phenomenon in Parkinson's disease. Relation to levodopa absorption and transport. N. Engl. J. Med. 310:483–488 (1984).PubMedGoogle Scholar
  17. 17.
    S. T. Gancher, J. G. Nutt, and W. R. Woodward. Peripheral pharmacokinetics of levodopa in untreated, stable and fluctuating parkinsonian patients. Neurology 37:940–944 (1987).PubMedGoogle Scholar
  18. 18.
    N. H. G. Holford. A size standard for pharmacokinetics. Clin. Pharmacokinet. 30:329–332 (1996).PubMedGoogle Scholar
  19. 19.
    J. G. Wagner. Linear Compartment Models. In: Fundamentals of Clinical Pharmacokinetics. 1st ed. Hamilton: Drug Intelligence Publications, INC (1975). pp. 57–128.Google Scholar
  20. 20.
    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).PubMedGoogle Scholar
  21. 21.
    N. H. G. Holford. MK Model, a Quantitative Modeling System for Pharmacologists. In. 5th ed.Cambridge, MA: Biosoft (1994).Google Scholar
  22. 22.
    G. A. F. Seber and C. J. Wild. Statistical Inference. In: Nonlinear Regression. New York: Wiley Interscience (1989), pp. 191–269.Google Scholar
  23. 23.
    G. Schwarz. Estimating the dimension of a model. Ann. Stat. 6:649–657 (1978).Google Scholar
  24. 24.
    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).PubMedGoogle Scholar
  25. 25.
    Z. Elkoshi. Concentration-effect relationship following levodopa/carbidopa administration to ''On-Off'' parkinsonian patients. Clin. Neuropharmacol. 17:147–164 (1994).Google Scholar
  26. 26.
    26. 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).CrossRefPubMedGoogle Scholar
  27. 27.
    J. G. Nutt, W. R. Woodward, and J. L. Anderson. The effect of carbidopa on the pharmacokinetics of intravenously administered levodopa. The mechanism of action in the treatment of parkinsonism. Ann. Neurol. 18:537–543 (1985).PubMedGoogle Scholar
  28. 28.
    28. R. J. Hardie, S. L. Malcolm, A. J. Lees, G. M. Stern, and J. G. Allen. The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on-off fluctuations. Br. J. Clin. Pharmacol. 22:429–436 (1986).PubMedGoogle Scholar
  29. 29.
    G. Fabbrini, J. Juncos, M. M. Mouradian, C. Serrati, and T. N. Chase. Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson's disease. Ann. Neurol. 21:370–376(1987).PubMedGoogle Scholar
  30. 30.
    M. Contin, R. Riva, P. Matinelli, and A. Baruzzi. Kinetic-dynamic relationship of oral levodopa: possible biphasic response after sequential doses in Parkinson's disease. Mov. Disord. 7:244–248 (1992).PubMedGoogle Scholar
  31. 31.
    E. J. Triggs, B. G. Charles, M. Contin, P. Martinelli, P. Cortelli, R. Riva, F. Albani, and A. Baruzzi. Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients. Eur. J. Clin. Pharmacol. 51:59–67 (1996).CrossRefPubMedGoogle Scholar
  32. 32.
    M. Contin, R. Riva, P. Martinelli, P. Cortelli, F. Albani, and A. Baruzzi. Longitudinal monitoring of the levodopa concentration-effect relationship in Parkinson's disease. Neurology 44:1287–1292 (1994).PubMedGoogle Scholar
  33. 33.
    J. G. Nutt and N. H. G. Holford. The response to levodopa in Parkinson's disease: imposing pharmacological law and order. Ann. Neurol. 39:561–573 (1996).PubMedGoogle Scholar
  34. 34.
    R. D. Sweet, J. E. Lee, H. E. Spiegel, and F. McDowell. Enhanced response to low dose of levodopa after withdrawal from chronic treatment. Neurology 22:520–525 (1972).PubMedGoogle Scholar
  35. 35.
    L. K. Direnfeld, R. G. Feldman, M. P. Alezander, and M. Kelly-Hayes. Is L-dopa drug holiday useful? Neurology 30:785–788 (1980).PubMedGoogle Scholar
  36. 36.
    W. J. Weiner, W. C. Koller, S. Perlik, P. A. Nausieda, and H. L. Klawans. Drug holiday and management of Parkinson's disease. Neurology 30:1257–1261 (1980).PubMedGoogle Scholar
  37. 37.
    C. G. Goetz, C. M. Tanner, and P. A. Nausieda. Weekly drug holiday in Parkinson's disease. Neurology 31:1460–1462 (1981).PubMedGoogle Scholar
  38. 38.
    G. P. Sechi, F. Tanda, and R. Mutani. Fatal hyperpyrexia after withdrawal of levodopa. Neurology. 34:249–251 (1984).PubMedGoogle Scholar
  39. 39.
    R. Mayeux, Y. Stern, K. Mulvey, and L. Cote. Reappraisal of temporary levodopa withdrawal (''Drug Holiday'') in Parkinson's disease. New England J. Medicine 313:724–728 (1985).Google Scholar
  40. 40.
    L. A. Wade and R. Katzman. 3-O-Methyldopa uptake and inhibition of L-dopa at the blood brain barrier. Life Sci. 17:131–136 (1975).CrossRefPubMedGoogle Scholar
  41. 41.
    M. M. Mouradian, J. L. Juncos, G. Fabbrini, J. Schlegel, J. J. Bartko, and T. N. Chase. Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part II. Ann. Neurol. 24:372–378 (1988).PubMedGoogle Scholar
  42. 42.
    R. de la Fuente-Fernandez, T. J. Ruth, V. Sossi, M. Schulzer, D. B. Calns, and A. J. Stoessl. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293:1164–1166 (2001).CrossRefPubMedGoogle Scholar
  43. 43.
    J. A. Straus and S. von Ammon Cavanaugh. Placebo effects. Issues for clinical practice in psychiatry and medicine. Psychosomatics 37:315–326 (1996).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • Phylinda L. S. Chan
    • 1
  • John G. Nutt
    • 2
  • Nicholas H. G. Holford
    • 1
  1. 1.Department of Pharmacology and Clinical PharmacologyUniversity of Auckland, AucklandNew Zealand
  2. 2.Department of Neurology and Physiology and PharmacologyPortland VA Medical Center and Oregon Health Sciences UniversityPortlandUSA

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