Routine outpatient L-dopa monitoring in elderly patients with Parkinson's disease

Age and Ageing,  March, 1994  by L.G. Copeland,  J. Dutton,  N.B. Roberts,  J.R. Playfer

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L. G. COPELAND, J. DUTTON, N. B. ROBERTS, J. R. PLAYFER

In an attempt to improve the therapeutic drug management of patients with Parkinson's disease, plasma L-dopa concentrations were measured by high-performance liquid chromatography and related to the post-dose time with reference to an established therapeutic range of 0.3-1.6 mg/l. The response to treatment was also assessed. One hundred and three samples were obtained at morning clinics from 53 elderly patients (mean age 72.5 years) taking an L-dopa/decarboxylase inhibitor combination. L-Dopa concentrations ranged from 0.01 to 3.6 mg/l. Fifty-nine values were within, 39 values were below and five values were above the therapeutic range. Three values were at or below the lower limit of the assay and probably indicated poor compliance. L-Dopa concentration was significantly negatively correlated with post-dose time for the dosage groups of 50 mg (p = 0.04), 100 mg (p = 0.0013), 200-250 mg (p = 0.055) and for the combined data (p = 0.005). Post-dose times were from 35 to 400 min, with the majority greater than 90 min, and it is likely that most of these corresponded to the post-peak phase of L-dopa absorption. There was a tendency for a good response to treatment to occur with values within and above the therapeutic range and for dyskinesia to be more common above the therapeutic range. It was concluded that plasma L-dopa measurement at known post-dose time, 90-360 minutes after the morning dose, can identify non-compliance, patients at risk of dose related side-effects and give useful information about the suitability of the L-dopa dose.

Introduction

L-Dopa (1)(2) in combination with a decarboxylase inhibitor (3)(4) is the standard treatment for Parkinson's disease. Patients will initially respond well to the drug but after a number of years a general deterioration can occur with the appearance of fluctuations in motor performance such as end-of-dose deterioration, on-off effect, and freezing episodes (5). Some of the fluctuations are related to the variable plasma L-dopa concentration (6) which results from its rapid absorption with time-to-peak concentration of 1-2 h and short elimination half-life of 45-120 minutes (7)(8)(9)(10). Also postsynaptic dopamine receptor change brought about by fluctuating L-dopa concentrations is thought to be a factor (11)(12)(13)(14). Studies with intravenous L-dopa have demonstrated that these fluctuations can be abolished if a constant plasma L-dopa concentration is maintained within specific limits (15)(16)(17)(18). Therapeutic ranges were thus established within which a maximal response was achieved. Concentrations above the range conferred no further benefit and dose related side-effects such as dyskinesias became more common. Using one of these therapeutic ranges (15) for reference we have investigated the potential role of single-timed L-dopa measurements in the management of elderly patients with Parkinson's disease in the outpatient department. In particular we wanted to examine compliance, doserelated side-effects and L-dopa dosage requirements.

Method

The study was carried out on 53 patients (Table I), 29 men and 24 women aged between 56 and 88 (mean 72.5) years with Parkinson's disease, taking L-dopa and a decarboxylase inhibitor, attending for their routine morning clinic appointments. Hoehn and Yahr scores (19) ranged from 2 to 4 (mean 2.9) and the duration of treatment ranged from 1 to 12 years (mean 6.2 years). The morning medication contained either 50 mg, 100 mg, 200 mg or 250 mg of L-dopa. Subjects were evaluated by a single physician (J.R.P.) and rated as showing non-response, minimal response and response to treatment at that time. The presence of dyskinesia was noted. The time of the L-dopa administration was noted and blood collected into lithiumheparin tubes and placed in iced water. The time of blood sampling minus the time of drug administration gave the post-dose time (PDT). The plasma was separated and stored at -30 to -40[degrees] within 2 h. L-Dopa concentration was measured by electrochemical detection following extraction on to alumina and separation by reversed phase high-performance liquid chromatography (20). [TABULAR DATA OMITTED]

Results

One hundred and three L-dopa concentrations were measured and ranged between 0.01 mg/l (the lower limit of the calibration of the assay) and 3.64 mg/l (Table I). Post-dose times were from 35 to 400 min (mean 210) with the majority (96) being 90 min or more. Compared with the chosen therapeutic range of 0.3 mg/l to 1.6 mg/l, 59 (57.3%) values were within, 39 (37.9%) were below and 5 (4.8%) were above this range. Three values were 0.01 or less and probably indicated non-compliance. One man who had a high L-dopa concentration was troubled with hypersexuality which resolved with dose reduction. Three of the patients with values above the range had dyskinesia. Using linear regression analysis there was a significant negative correlation (Figure 1) between L-dopa concentration and post-dose time for all the data (p = 0.005), the 50 mg (p = 0.04) and 100 mg groups (p = 0.0013). This relationship approached significance in the 200-250 mg group (p = 0.055). In order to involve the known variables of body weight and post-dose time the L-dopa dose corrected for body weight (mg/kg) was divided by the post-dose time (PDT) and a highly significant positive correlation (p < 0.001) was found with the L-dopa concentration (Figure 2).