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.

Arbetslöshet som en icke önskvärd konsekvens av socialbidrag : Resultat från en tidsserieanalys på befolkningsnivå i Sverige 1946–1990

Unemployment as an unintended consequence of social assistance recipiency: results from a time-series analysis of aggregated population data Does the frequency of unemployment have a tendency to increase the number of social assistance recipients, or does the relationship work the other way around? This article utilizes Swedish annual data on aggregated unemployment and means-tested social assistance recipiency in the period 1946–1990 and proposes a multiple time-series approach based on vector error-correction modelling to establish the direction of influence. First, we show that rates of unemployment and receipt of social assistance is co-integrated. Second, we demonstrate that adjustments to the long-run equilibrium are made through adjustments of the unemployment. This indicates that the level of unemployment reacts to changes in rates of social assistance recipiency rather than vice versa. It is also shown that lagged changes in the level of unemployment do not predict changes in rates of social assistance recipients in short-term. Together these findings demonstrate that the number of social assistance recipients does increase the number of unemployed in a period characterized by low unemployment and high employment.