Levodopa Therapy Monitoring in Patients With Parkinson Disease: a Kinetic–Dynamic Approach

Abstract

The authors assessed differences in both therapeutic and dyskinesia-matched concentrations of levodopa by kinetic-dynamic modeling in a large cohort of patients with Parkinson disease grouped by severity of symptoms. The goal was to provide a kinetic-dynamic approach to levodopa therapy monitoring to assist treating physicians in rationalizing patients' drug schedules in line with disease progression. Eighty-six patients, grouped according to Hoehn & Yahr (H&Y) clinical stage (H&Y I, n = 23; II, n = 25; III; n = 25; IV, n = 13) enrolled in the study. After a 12-hour levodopa washout each patient was examined using a standard oral levodopa test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects, and dyskinesia ratings. The kinetic-dynamic modeling for both effects was carried out according to the "link" effect compartment model and sigmoidal pharmacodynamic model. Levodopa plasma kinetics did not differ among patient groups. Duration of motor response was significantly (p < 0.001) curtailed in patients in advanced clinical stages whereas dyskinesia duration showed minor changes among the three affected groups (H&Y II, III, and IV). Median effective concentrations (EC 50 ) were increased at the more advanced clinical stage (p < 0.001), from a median 0.2 microg/mL in patients at H&Y stage I to 0.9 microg/mL in patients at H&Y stage IV, whereas the maximum effect showed less consistent changes among the four groups. Intrasubject levodopa therapeutic concentrations were lower than values for dyskinesias in patients at the moderate stage of the disease, equaling dyskinesia-matched drug concentrations in the more affected patients. These findings are in line with previous observations of major changes in levodopa concentration-effects relationship with disease progression and support a stratification of patients with Parkinson disease according to kinetic-dynamic modeling. From a practical point of view, knowledge of individual patients' kinetic-dynamic variables can help the physician assess patients' clinical needs objectively and optimize levodopa dosing according to disease progression.

Pharmacokinetics of levodopa

“…2), partly explaining the appearance of the ''wearing-off'' phenomena [38]. Moreover, the increase in EC 50 values suggests that a standard dose can maintain plasma drug concentrations above a ''therapeutic threshold'' for a shorter period over time, also contributing to the shortening of the effect [15].…”

“…3) should be taken into account in treating motor fluctuations. The common strategy of reducing the size of each levodopa dose and increasing the frequency of administration can be matched to lower drug levels and result in briefer and more erratic motor responses, depending on even slight variations in levodopa plasma concentrations that are closer to threshold values [15,37].…”

“…Reproduced with permission by Lippincott, Williams and Wilkins, a Wolters Kluwer company Fig. 3 Mean levodopa plasma concentration profile (n = 86) superimposed on different ''thresholds'' (EC 50 , median values) of levodopa therapeutic and dyskinetic concentrations in patients grouped by H&Y stage [15]. Adapted with permission by Lippincott, Williams and Wilkins, a Wolters Kluwer company and tailoring of plasma levodopa concentrations in patients with complicated and complex ''wearing-off'' phenomena [13].…”

“…Knowledge of individual patients' levodopa kinetic-dynamic relationship can contribute to rationalise drug treatment according to disease progression [15]. …”

Assessing dopaminergic function in Parkinson?s disease: levodopa kinetic-dynamic modeling and SPECT

“…Inclusion criteria were diagnosis of PD according to the Parkinson's Disease Society Brain Bank clinical criteria [12], chronic (> 3 months) levodopa plus carbidopa or benserazide therapy, and a positive response to an oral levodopa test previously standardized in our laboratory [8]. Criteria for a positive response were a > 15 % increase in tapping score and a > 25 % improvement in walking time.…”