Modeling the short- and long-duration responses to exogenous levodopa and to endogenous levodopa production in Parkinson's disease

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 E-max 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, T-eqf), slow equilibration (T-eqs) and dopa synthesis (T-eqd)), 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.