The pharmacokinetic profile of the "first ever" oral dose of levodopa in de novo patients with Parkinson's disease

To understand the delay in the clinical benefit that commonly occurs after initiation of levodopa (L-Dopa) treatment, we examined the pharmacokinetic profile of L-Dopa after the first oral dose ever taken of L-Dopa/carbidopa in untreated patients with Parkinson's disease and followed these parameters after 1 month of treatment. This was performed in correlation with the clinical therapeutic effect. Plasma levels of L-Dopa were measured with use of high-performance liquid chromatography with electrochemical detection after administration of the "first ever" 125 mg L-Dopa/12.5 mg carbidopa tablet in 15 patients with de novo Parkinson's disease (mean age, 69 ± 11 y, mean disease duration, 1.5 ± 0.8 years). Blood samples were drawn before administration and thereafter at various intervals for a period of 4 hours. Repeated measurements after the same oral dose were performed after 1 month of continued therapy with L-Dopa/carbidopa 125/12.5 mg three times daily. Patients were clinically evaluated by unified Parkinson's disease rating scale motor scores. There was a modest clinical improvement after 1 month of continuous L-Dopa treatment (motor scores, 13.1 ± 11.6 vs. 17.6 ± 11.7; p < 0.01). Peak plasma L-Dopa levels and area under the curve did not differ significantly between the first-ever dose and after 1 month of continuous treatment (0.9 ± 0.1 vs. 1.0 ± 0.1 μg/mL and 66.0 ± 30.9 vs. 86.2 ± 34.9 μg/mL, respectively; p < 0.1. There was also no change in time to peak levels between measurements. Results indicate that the first-ever dose of oral L-Dopa is well absorbed and that pharmacokinetic mechanisms such as reduced absorption of L-Dopa probably do not play a major role in the initial delay in clinical response to oral L-Dopa/carbidopa in patients with Parkinson's disease. The latter phenomena may be linked to central pharmacodynamic mechanisms.