The most severe parkinsonian patients are most improved with duodenal levodopa infusion

Objectives:To find variables correlated to improvement with intraduodenal levodopa/carbidopa infusion (Duodopa) in order to identify potential candidates for this treatment. Two clinical studies comparing Duodopa with oral treatments in patients with advanced Parkinson’s disease have shown significant improvement in percent on-time on a global treatment response scale (TRS) based on hourly and half-hourly clinical ratings and in median UPDRS scores.Methods:Data from study 1 comparing infusion with Sinemet CR (12 patients, Nyholm et al, Clin Neuropharmacol 2003; 26(3): 156-163) and study 2 comparing infusion with individually optimised conventional combination therapies (18 patients, Nyholm et al, Neurology, in press) were used. Measures of severity were defined as total UPDRS score and scores for sections II and III, percent functional on-time and mean squared error of ratings on the TRS and as mean of diary questions about mobility and satisfaction (only study 2). Absolute improvement was defined as difference in severity, and relative improvement was defined as percent absolute improvement/severity on oral treatment. Pearson correlation coefficients between measures of improvement and other variables were calculated.Results:Correlations (r2>0.28, p<0.05) between severity during oral treatment and absolute improvement on infusion were found for: Total UPDRS, UPDRS III and TRS ratings (studies 1 and 2) and for diary question 1 (mobility) and UPDRS II (study 2). Correlation to relative improvement was found for total UPDRS (study 2, r2=0.47). Figure 1 illustrates absolute improvement in total UPDRS vs. total UPDRS during oral treatment (study 2).Conclusion:Correlating different measures of severity and improvement revealed that patients with more severe symptoms were most improved and that the relation between severity and improvement was linear within the studied groups. The result, which was reproducible between two clinical studies, could be useful when deciding candidates for the treatment.

Analysis of response to enteral infusion of levodopa in patients with Parkinson's disease

Objective: We present a new evaluation of levodopa plasma concentrations and clinical effects during duodenal infusion of a levodopa/carbidopa gel (Duodopa ) in 12 patients with advanced Parkinson s disease (PD), from a study reported previously (Nyholm et al, Clin Neuropharmacol 2003; 26(3): 156-163). One objective was to investigate in what state of PD we can see the greatest benefits with infusion compared with corresponding oral treatment (Sinemet CR). Another objective was to identify fluctuating response to levodopa and correlate to variables related to disease progression. Methods: We have computed mean absolute error (MAE) and mean squared error (MSE) for the clinical rating from -3 (severe parkinsonism) to +3 (severe dyskinesia) as measures of the clinical state over the treatment periods of the study. Standard deviation (SD) of the rating was used as a measure of response fluctuations. Linear regression and visual inspection of graphs were used to estimate relationships between these measures and variables related to disease progression such as years on levodopa (YLD) or unified PD rating scale part II (UPDRS II).Results: We found that MAE for infusion had a strong linear correlation to YLD (r2=0.80) while the corresponding relation for oral treatment looked more sigmoid, particularly for the more advanced patients (YLD>18).

A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion

Objective Levodopa in presence of decarboxylase inhibitors is following two-compartment kinetics and its effect is typically modelled using sigmoid Emax models. Pharmacokinetic modelling of the absorption phase of oral distributions is problematic because of irregular gastric emptying. The purpose of this work was to identify and estimate a population pharmacokinetic- pharmacodynamic model for duodenal infusion of levodopa/carbidopa (Duodopa®) that can be used for in numero simulation of treatment strategies. Methods The modelling involved pooling data from two studies and fixing some parameters to values found in literature (Chan et al. J Pharmacokinet Pharmacodyn. 2005 Aug;32(3-4):307-31). The first study involved 12 patients on 3 occasions and is described in Nyholm et al. Clinical Neuropharmacology 2003:26:156-63. The second study, PEDAL, involved 3 patients on 2 occasions. A bolus dose (normal morning dose plus 50%) was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function from video recordings on a treatment response scale between -3 and 3, where -3 represents severe parkinsonism and 3 represents severe dyskinesia.) were repeatedly collected until the clinical effect was back at baseline. At this point, the usual infusion rate was started and sampling continued for another two hours. Different structural absorption models and effect models were evaluated using the value of the objective function in the NONMEM package. Population mean parameter values, standard error of estimates (SE) and if possible, interindividual/interoccasion variability (IIV/IOV) were estimated. Results Our results indicate that Duodopa absorption can be modelled with an absorption compartment with an added bioavailability fraction and a lag time. The most successful effect model was of sigmoid Emax type with a steep Hill coefficient and an effect compartment delay. Estimated parameter values are presented in the table. Conclusions The absorption and effect models were reasonably successful in fitting observed data and can be used in simulation experiments.

Analysis of tapping test results in a test battery for advanced PD patients

Objective: To compare results from various tapping tests with diary responses in advanced PD. Background: A home environment test battery for assessing patient state in advanced PD, consisting of diary assessments and motor tests was constructed for a hand computer with touch screen and mobile communication. The diary questions: 1. walking, 2. time in off , on and dyskinetic states, 3. off at worst, 4. dyskinetic at worst, 5. cramps, and 6. satisfied with function, relate to the recent past. Question 7, self-assessment, allows seven steps from -3 ( very off ) to +3 ( very dyskinetic ) and relate to right now. Tapping tests outline: 8. Alternately tapping two fields (un-cued) with right hand 9. Same as 8 but using left hand 10. Tapping an active field (out of two) following a system-generated rhythm (increasing speed) with the dominant hand 11. Tapping an active field (out of four) that randomly changes location when tapped using the dominant hand Methods: 65 patients (currently on Duodopa, or candidates for this treatment) entered diary responses and performed tapping tests four times per day during one to six periods of seven days length. In total there were 224 test periods and 6039 test occasions. Speed for tapping test 10 was discardedand tests 8 and 9 were combined by taking means. Descriptive statistics were used to present the variation of the test variables in relation to self assessment (question 7). Pearson correlation coefficients between speed and accuracy (percent correct) in tapping tests and diary responses were calculated. Results: Mean compliance (percentage completed test occasions per test period) was 83% and the median was 93%. There were large differences in both mean tapping speed and accuracy between the different self-assessed states. Correlations between diary responses and tapping results were small (-0.2 to 0.3, negative values for off-time and dyskinetic-time that had opposite scale directions). Correlations between tapping results were all positive (0.1 to 0.6). Conclusions: The diary responses and tapping results provided different information. The low correlations can partly be explained by the fact that questions related to the past and by random variability, which could be reduced by taking means over test periods. Both tapping speed and accuracy reflect the motor function of the patient to a large extent.