Pharmacodynamic modeling of concentration‐effect relationships after controlled‐release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease

Nelson, M. V.; Berchou, Richard; Witt, P. A. Le; Kareti, Das; Galloway, M. P.

doi:10.1212/wnl.40.1.70

Cited by 35 publications

(23 citation statements)

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“…different score systems for the motor response), PK-PD studies on levodopa IIS,i6, [39][40][41] have demonstrated almost consistent findings. All studies prove the E max model to be suitable for describing the C-E relationship of levodopa.…”

Section: Studies On the Pk-po Relationship Of Levodopamentioning

confidence: 78%

Concentration-Effect Relationship of Levodopa in Patients with Parkinson's Disease

Harder

Baas

Rietbrock

1995

Clinical Pharmacokinetics

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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 cl...

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Section: Studies On the Pk-po Relationship Of Levodopamentioning

confidence: 78%

Concentration-Effect Relationship of Levodopa in Patients with Parkinson's Disease

Harder

Baas

Rietbrock

1995

Clinical Pharmacokinetics

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“…Analyses were first performed in strata defined by respondent type (proxy, nonproxy) and pooled only if results were similar. 36 Because smoking behavior may have changed as the result of early, undiagnosed PD, analyses also were performed for the periods 10 years and 20 years before the index date. Analyses of "total" tobacco exposure, including cigarettes, cigars, pipes, and chewing tobacco, also were performed for each of these strata.…”

mentioning

confidence: 99%

Smoking and Parkinson’s disease in twins

Tanner

Goldman²,

Aston³

et al. 2002

Neurology

183

112

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Within twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.

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“…However, acute tolerance to levodopa does not appear to be the underlying cause as proteresis (i.e. clockwise hysteresis) was not present in the plasma drug concentrationeffect plots, and this phenomenon has not been reported by other authors who applied PK/PD-modeling to levodopa [1][2][3].…”

Section: Concentration-effect-analysismentioning

confidence: 74%

“…The equilibration half life of the effect compartment has been reported to about 30 min and a similar value was observed in our study when the IR preparation was given. Nelson et al [2] investigated the pharmacokinetic/dynamic relationship of levodopa after single dose administration of a CR-preparation. The mean EC50 was about 900 ng ml-' for improvement of walking speed and 1600 ng ml-' for the results of a finger tapping test.…”

Section: Concentration-effect-analysismentioning

confidence: 99%

“…Studies on the concentration-effect relationship of reactions when plasma concentrations declined below levodopa in patients with Parkinson's disease have this level [1][2][3]. Controlled release (CR) preparademonstrated an immediate onset of the motor tions of levodopa should provide prolonged plasma response to levodopa when a threshold plasma conconcentrations above this 'therapeutic' threshold centration was exceeded and the appearance of off- [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Concentration‐effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.

Harder

Baas

Bergemann

et al. 1995

Brit J Clinical Pharma

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1 The relationship between plasma concentration of levodopa and motor-response was investigated in 12 patients with Parkinson's disease who showed marked response fluctutations, after a single oral dose of an immediate release (IR) formulation (100 mg levodopa/25 mg benserazide) 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 (CURSE) 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-' h per mg and 23.2 (± 4.6 s.d.) ng ml-' h per mg after the CR-formulation. Cmax was 1714 (± 1027 s.d.) ng ml-' after the IR-formulation and 1494 (± 383 s.d.) ng ml-' after the CR-formulation. 4 With both preparations, the maximal response to levodopa (Emax) was a decrease in the CURS£ rating of about 27 scores. Estimates of the EC50 of levodopa were 495 (± 144 s.d.) ng ml-' (IR) and 1024 (± 502 s.d.) ng ml-' (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%-Cl: 1.12-2.04, point estimator 1.53). 5 The difference in the responsiveness after the CR-formulation might be due to the increase in the concentrations of 3-O-methyldopa which rose from 5410 (± 2360 s.d.) ng ml-' pre-dose to 6126 (± 2660 s.d.) ng ml-' post-dose after the IR-form and from 5146 (± 2292 s.d.) ng ml-' pre-dose to 6873 (± 2830 s.d.) ng ml-' postdose after the CR-form (95%-CI for the difference Cmax-Cmin: 2.04-3.88, point estimator 2.63).6 Although the peak response (i.e. Emax) was not different after the two formulations, a gain in the duration of the motor response, which might be provided by sustained plasma concentrations of levodopa after the CR-preparation was offset partially by the apparent doubling of the threshold level (EC50).

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Pharmacodynamic modeling of concentration‐effect relationships after controlled‐release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease

Cited by 35 publications

References 0 publications

Concentration-Effect Relationship of Levodopa in Patients with Parkinson's Disease

Concentration-Effect Relationship of Levodopa in Patients with Parkinson's Disease

Smoking and Parkinson’s disease in twins

Concentration‐effect relationship of levodopa in patients with Parkinson's disease after oral administration of an immediate release and a controlled release formulation.

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