Routine outpatient L-dopa monitoring in elderly patients with Parkinson’s disease
L.G. Copeland
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).
In 43 patients studied in detail, dyskinesia was observed in association with varied L-dopa concentrations but became more common with increasing concentration (Table II). The three grades of response to L-dopa were found in association with all levels of L-dopa concentration but non-response was more common in association with values below the therapeutic range and response associated with values within and above the range (Table III).
Table II. Number of patients with dyskinesia (43 studied) with
reference to the therapeutic range
Therapeutic range Below Within Above
Number of patients 21 17 5
Mean Hoehn and Yahr score 2.7 2.7 2.8
Mean L-dopa dose (mg) 76.2 120 200
No. (%) with dyskinesia 5(24) 7(41) 3(60)
Table III. Number of patients in three grades of clinical
response with
reference to the therapeutic range (43 studied)
Response
Present Minimal Absent
Values below range (n=21)(%) 6(28) 5(24) 10(48)
Values within range (n=17)(%) 14(82) 0(0) 3(18)
Values above range (n=5)(%) 3(60) 1(20) 1(20)
Discussion
The plasma L-dopa concentrations showed a wide spread of values in keeping with the previously observed inter-patient variability in L-dopa pharmacokinetics (21)(22). Nevertheless significant negative correlation was found between the L-dopa concentration and the post-dose time. In view of this and the fact that most of the post-dose times were greater than 90 min it is likely that the majority of the samples were taken in the post-peak period of L-dopa absorption. During this period our results showed a linear relationship between falling L-dopa concentration and PDT. From this it follows that the plasma L-dopa concentrations can be interpreted in a general way, e.g. an L-dopa concentration below the therapeutic range 2 h after the morning medication would indicate that the dose is inadequate if the medication is taken 4-hourly. However, such a relationship may not be found later in the day because of accumulative L-dopa doses. Unfortunately there are factors which complicate the interpretation of single L-dopa measurements such as delayed absorption, failure of absorption and twin-peaked absorption (23). L-Dopa measurements at regular intervals (an L-dopa profile) would give more precise information.
The highly significant positive correlation observed between the L-dopa concentration and the ratio of dose in milligrams per kilogram of body weight per minute of post-dose time suggests that both dose and body weight are factors in the inter-patient variability in L-dopa concentration. Fifty-seven per cent of values were within the therapeutic range suggesting an adequate morning dose in these patients. Thirty-eight per cent of values were below the therapeutic range, of which a large proportion followed 50 mg of L-dopa suggesting that such a dose was inadequate. This may not be important in early disease where smaller infrequent doses are effective or if the L-dopa is taken frequently. Following the 100 mg dose most of the values were within the therapeutic range, one was marginally above the range and a number were below. All but one of the values following 200-250 mg were above the lower limit of the range and four were above the upper limit. It would seem therefore that the optimal individual dose lies between 100 and 250 mg with the possibility of unnecessarily high L-dopa concentrations after 200-250 mg. Only three values were below the threshold of the calibration of the assay suggesting poor compliance. In view of the short half-life of L-dopa, the subjects need only to have omitted that morning’s dose. Lack of absorption is an alternative explanation. Therefore compliance, as judged by the patients taking their tablets the morning of the clinic, was good in this group of patients. Compliance may be better evaluated by simultaneously measuring the L-dopa metabolite 3-methoxy-dopa which has a longer half-life (24). Dyskinesia was found over a wide range of L-dopa concentrations, but of the five values above the therapeutic range three were associated with dyskinesia and one with hypersexuality, which are known to be dose-related side-effects. Dyskinesias may occur following peaks of L-dopa concentration and subside as the concentration declines but may also occur after low L-dopa concentration. Random L-dopa measurements may miss these peaks unless the blood samples are taken at the time of a suspected side-effect. There is a lag period between plasma L-dopa concentration and clinical effect and so a peak value could be missed although the concentration is still likely to be raised. To overcome such problems an L-dopa profile could be used (25). The three grades of response were found in association with variable L-dopa concentrations (26)(27)(28)(29), but there was a trend for non-response to be more common below the therapeutic range and response to be more common above the lower limit of the therapeutic range.
In conclusion, in elderly patients with Parkinson’s disease, especially those experiencing fluctuations in control of the disease, timed plasma L-dopa measurements taken 90-360 min after the morning dose of L-dopa can be used to check compliance, and give useful information to be used in planning a patient’s drug regimen. High concentrations causing side-effects such as dyskinesia can be easily identified.
References
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Authors’ addresses
L. G. Copeland(*), J. R. Playfer Department of Geriatric Medicine,
J. Dutton, N. B. Roberts Department of Clinical Chemistry, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XW (*)Address correspondence to: Department of Geriatric Medicine, Dudley Road Hospital, Dudley Road, Birmingham B18 7QH
Received in revised form 13 June 1993
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