Pharmacodynamic modeling of oral levodopa in Parkinson's disease

University of Bologna, Bolonia, Emilia-Romagna, Italy
Annals of Neurology (Impact Factor: 9.98). 11/2001; 50(5):687-8. DOI: 10.1002/ana.1268
Source: PubMed
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    ABSTRACT: 1. The relationship between plasma concentration of levodopa and motor-response was investigated in 12 patients with Parkinson's disease who showed marked response fluctuations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg genserazide) and a controlled release (CR) formulation (300 mg levodopa/75 mg benserazide), using a double-blind, randomized, cross-over design. 2. The sum score of the Columbia University Rating Scale (CURS sigma) was used for pharmacodynamic assessment. A sigmoidal Emax-model was fitted to the data using a semiparametric pharmacokinetic/dynamic approach. 3. The dose-corrected AUC of levodopa after the IR-formulation was 27.5 (+/- 9.1 s.d.) ng ml-1 h per mg and 23.2 (+/- 4.6 s.d.) ng ml-1 h per mg after the CR-formulation. Cmax was 1714 (+/- 1027 s.d.) ng ml-1 after the IR-formulation and 1494 (+/- 383 s.d.) ng ml-1 after the CR-formulation. 4. With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS sigma rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (+/- 144 s.d.) ng ml-1 (IR) and 1024 (+/- 502 s.d.) ng ml-1 (CR), respectively (95%-CI: 1.51-2.66, point estimator 1.95). The mean duration of the motor response was 1.9 (+/- 0.5 s.d.) h (IR) and 2.8 (+/- 0.7 s.d.) h (CR), respectively (95%-CI: 1.12-2.04, point estimator 1.53).(ABSTRACT TRUNCATED AT 250 WORDS)
    British Journal of Clinical Pharmacology 02/1995; 39(1):39-44. DOI:10.1111/j.1365-2125.1995.tb04407.x · 3.88 Impact Factor
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    ABSTRACT: Studies on the concentration-effect relationship of levodopa in Parkinson's disease have established that: (1) in patients with a fluctuating response to levodopa, concentration-effect profiles are steeper and markedly shifted to the right (i.e. potency is decreased) compared with those patients whose symptoms are adequately controlled; (2) with controlled-release (CR) preparations, the concentration-effect relationship indicates a decreased potency compared with conventional immediate-release (IR) preparations; and (3) coadministration of a dopamine receptor agonist (even at a subclinical dose) enhances the potency of levodopa. These findings support some current hypotheses on the origin of, and the pathophysiological process underlying, response fluctuations. In patients with response fluctuations, metabolism of levodopa and storage of dopamine in the striatum are reduced. Levodopa is decarboxylated in the extracellular space, with the result that dopamine is released directly to the effect site. Thus, without dopamine storage acting as a buffer between levodopa metabolism and dopaminergic effect, the decline in motor response closely follows the decrease in levodopa concentrations. Even small fluctuations of levodopa concentrations around the EC50 value (the concentration threshold necessary to produce a motor response) might be followed by response fluctuations. Patients with Parkinson's disease who do not have response fluctuations exhibit a residual capacity of production and storage of endogenous dopamine; thus, lower amounts of 'exogenous' dopamine (formed by decarboxylation of levodopa) are required. The storage buffer is responsible for a time lag between decline in peripheral plasma concentrations of levodopa and dopamine-induced motor response. Low doses of a dopamine receptor agonist increase the basal tonus of the striatum, but do not reach the threshold concentration for triggering a motor response. Because of the dichotomic character of the motor response, patients do not switch from an 'off' (not responding) phase to an 'on' (responding) phase. However, lower amounts of exogenous dopamine released in the synaptic cleft will be necessary to induce response. To date, pharmacokinetic-pharmacodynamic modelling does not give a clear answer as to whether response fluctuations are additionally induced by receptor desensitisation or inhibition of the active transport of levodopa across the blood-brain barrier by the main metabolite of levodopa, 3-O-methyldopa. Nevertheless, there is some evidence that higher plasma concentrations of levodopa are required for similar motor effects when CR preparations are compared with IR preparations. Attempts have been made to establish therapeutic drug monitoring of levodopa in patients with response fluctuations. The interindividual variability of EC50 values in single studies is relatively low (10% to a maximum of 50%), which might allow specification of a 'population' threshold plasma concentration (i.e. a minimal effective plasma concentration required to obtain clinical effects). However, considering the short elimination half-life of levodopa, it seems doubtful whether such target drug concentrations can be maintained as steady-state. A marked prolongation of the dosage interval with CR preparations might be limited by the higher threshold concentrations of levodopa necessary to maintain clinical effects.
    Clinical Pharmacokinetics 11/1995; 29(4):243-56. DOI:10.2165/00003088-199529040-00004 · 5.05 Impact Factor
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    ABSTRACT: To assess patterns, prevalence, and risk factors of motor fluctuations in an unselected population of Parkinson's disease patients attending Movement Disorders Clinic of a tertiary hospital. Eighty patients with Parkinson's disease were interviewed and data about their clinical characteristics, motor fluctuations, i.e. dyskinesia, dystonia, motor blocks and details of drug therapy, were collected. Forty patients had at least one type of motor fluctuation. Twenty three patients had motor blocks, 20 had dyskinesia and 11 had dystonia. Interval between onset of symptom and start of levodopa therapy and duration of levodopa therapy correlated with presence of motor fluctuations in general and to dyskinesia in particular. Patients with dyskinesia had younger age of onset of disease. Motor blocks showed a positive relationship to duration of disease. Fifty percent of unselected patients of Parkinson's disease had motor fluctuations after a mean duration of 5 years of illness. Early initiation and longer duration of levodopa therapy were identified as risk factors for motor fluctuations. Younger patients had more risk of developing dyskinesias. Motor blocks were more common in patients with a longer duration of illness.
    Journal of the Neurological Sciences 06/1999; 165(1):18-23. DOI:10.1016/S0022-510X(99)00052-0 · 2.47 Impact Factor
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