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.

Road network and GPS tracking with data processing and quality assessment

GPS technology has been embedded into portable, low-cost electronic devices nowadays to track the movements of mobile objects. This implication has greatly impacted the transportation field by creating a novel and rich source of traffic data on the road network. Although the promise offered by GPS devices to overcome problems like underreporting, respondent fatigue, inaccuracies and other human errors in data collection is significant; the technology is still relatively new that it raises many issues for potential users. These issues tend to revolve around the following areas: reliability, data processing and the related application. This thesis aims to study the GPS tracking form the methodological, technical and practical aspects. It first evaluates the reliability of GPS based traffic data based on data from an experiment containing three different traffic modes (car, bike and bus) traveling along the road network. It then outline the general procedure for processing GPS tracking data and discuss related issues that are uncovered by using real-world GPS tracking data of 316 cars. Thirdly, it investigates the influence of road network density in finding optimal location for enhancing travel efficiency and decreasing travel cost. The results show that the geographical positioning is reliable. Velocity is slightly underestimated, whereas altitude measurements are unreliable.Post processing techniques with auxiliary information is found necessary and important when solving the inaccuracy of GPS data. The densities of the road network influence the finding of optimal locations. The influence will stabilize at a certain level and do not deteriorate when the node density is higher.