Modeling the Short- and Long-Duration Responses to Exogenous Levodopa and to Endogenous Levodopa Production in Parkinson's Disease
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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.
- 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).
- 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).
- 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).
- 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).
- C. L. Comella, J. Bohmer, and G. T. Stebbins. Sleep benefit in Parkinson's disease (Abstract). Mov. Disord. 45:A286 (1995).
- 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).
- 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).
- J. G. Nutt, J. H. Carter, and W. R. Woodward. Long-duration response to levodopa. Neurology 45:1613–1616 (1995).
- 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).
- D. E. Bateman, K. Levett, and C. D. Marsden. Sleep benefit in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 67:384–385 (1999).
- 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).
- 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).
- 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).
- 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).
- D. J. Gelb, E. Oliver, and S. Gilman. Diagnostic criteria for Parkinson disease. Arch. Neurol. 56:33–39 (1999). CrossRef
- 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).
- 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).
- N. H. G. Holford. A size standard for pharmacokinetics. Clin. Pharmacokinet. 30:329–332 (1996).
- J. G. Wagner. Linear Compartment Models. In: Fundamentals of Clinical Pharmacokinetics. 1st ed. Hamilton: Drug Intelligence Publications, INC (1975). pp. 57–128.
- 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).
- N. H. G. Holford. MK Model, a Quantitative Modeling System for Pharmacologists. In. 5th ed.Cambridge, MA: Biosoft (1994).
- G. A. F. Seber and C. J. Wild. Statistical Inference. In: Nonlinear Regression. New York: Wiley Interscience (1989), pp. 191–269.
- G. Schwarz. Estimating the dimension of a model. Ann. Stat. 6:649–657 (1978).
- 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).
- Z. Elkoshi. Concentration-effect relationship following levodopa/carbidopa administration to ''On-Off'' parkinsonian patients. Clin. Neuropharmacol. 17:147–164 (1994).
- 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). CrossRef
- 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).
- 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).
- 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).
- 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).
- 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). CrossRef
- 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).
- 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).
- 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).
- L. K. Direnfeld, R. G. Feldman, M. P. Alezander, and M. Kelly-Hayes. Is L-dopa drug holiday useful? Neurology 30:785–788 (1980).
- 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).
- C. G. Goetz, C. M. Tanner, and P. A. Nausieda. Weekly drug holiday in Parkinson's disease. Neurology 31:1460–1462 (1981).
- G. P. Sechi, F. Tanda, and R. Mutani. Fatal hyperpyrexia after withdrawal of levodopa. Neurology. 34:249–251 (1984).
- 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).
- 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). CrossRef
- 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).
- 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). CrossRef
- J. A. Straus and S. von Ammon Cavanaugh. Placebo effects. Issues for clinical practice in psychiatry and medicine. Psychosomatics 37:315–326 (1996).
- Modeling the Short- and Long-Duration Responses to Exogenous Levodopa and to Endogenous Levodopa Production in Parkinson's Disease
Journal of Pharmacokinetics and Pharmacodynamics
Volume 31, Issue 3 , pp 243-268
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- Parkinson's disease
- long-duration response
- Industry Sectors
- Author Affiliations
- 1. Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
- 2. Department of Neurology and Physiology and Pharmacology, Portland VA Medical Center and Oregon Health Sciences University, Portland, USA