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A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biomedical Informatics and Engineering.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
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2011 (English)In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 34, no 2, 61-65 p.Article in journal (Refereed) Published
Abstract [en]

Objective: The purpose of this work was to identify and estimate a population pharmacokinetic-pharmacodynamic model for duodenal infusion of a levodopa/carbidopa gel (Duodopa) to examine pharmacological properties of this treatment.

Methods: The modeling involved pooling data from 3 studies (on advanced Parkinson disease) and fixing some parameters to values found in literature. The first study involved 12 patients studied on 3 occasions each and was previously published. The second study involved 3 patients on 2 occasions. A bolus dose was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function on a 7-point treatment response scale ranging from "very off" to "very hyperkinetic") were collected until the clinical effect returned to baseline. The third study involved 5 patients on 3 occasions receiving 5 different dose levels. Different structural models were evaluated using the nonlinear mixed-effects modeling program NONMEM VI. Population mean parameter values, and interindividual, interoccasion, and residual variabilities were estimated.

Results: Absorption of the levodopa/carbidopa gel can be adequately described with first-order absorption with bioavailability and lag time. Estimated population parameter values were a mean absorption time of 28.5 minutes, a lag time of 2.9 minutes, and a bioavailability of 88%. The pharmacodynamic model for motor ratings had the following population values: a half-life of effect delay of 21 minutes, a concentration at 50% effect of 1.55 mg/L, an E-max of 2.39 U on the treatment response scale, and a sigmoidicity of the E-max function of 11.6.

Conclusions: For the typical unmedicated subject, it will take 51.4 minutes until the peak levodopa effect is reached after a bolus dose. This delay is, like the magnitude of the effect, highly variable in this patient group. The residual error magnitudes of 20% for levodopa concentrations and 0.92 U (SD) for motor ratings indicate that the models developed provide predictions of a relevant quality. The developed model may be a first step toward model-guided treatment individualization of duodenal infusion of levodopa.

Place, publisher, year, edition, pages
2011. Vol. 34, no 2, 61-65 p.
Keyword [en]
Levodopa, infusion, Parkinson’s disease, pharmacokinetic, pharmacodynamic
National Category
Medical and Health Sciences
Research subject
Medical Informatics; Neurology; Pharmacokinetics and Drug Therapy
URN: urn:nbn:se:uu:diva-132634DOI: 10.1097/WNF.0b013e31820b570aISI: 000288445400002PubMedID: 21297456OAI: oai:DiVA.org:uu-132634DiVA: diva2:358656
Available from: 2010-10-23 Created: 2010-10-23 Last updated: 2014-01-29Bibliographically approved
In thesis
1. Decision Support for Treatment of Patients with Advanced Parkinson’s Disease
Open this publication in new window or tab >>Decision Support for Treatment of Patients with Advanced Parkinson’s Disease
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Beslutsstöd för behandling av patienter med avancerad Parkinsons sjukdom
Abstract [en]

The overall aim of this thesis was to develop, deploy and evaluate new IT-based methods for supporting treatment and assessment of treatment of advanced Parkinson’s disease. In this condition a number of different motor and non-motor symptoms occur in episodes of varying frequency, duration and severity. In order to determine outcome of treatment changes, repeated assessments are necessary. Hospitalization for observation is expensive and may not be representative for the situation at home. Paper home diaries have questionable reliability and storage and retrieval of results are problematic. Approaches for monitoring using wearable sensors are unable to address important non-motor symptoms.

A test battery system consisting of both self-assessments of symptoms and motor function tests was constructed for a touch screen mobile phone. Tests are performed on several occasions per day during test periods of one week. Data is transmitted over the mobile net to a central server where summaries in different symptom dimensions and an overall test score per patient and test period are calculated. There is a web application that graphically presents the results to treating clinical staff. As part of this work, a novel method for assessment of spiral drawing impairment useful during event-driven sampling was developed. To date, the system has been used by over 100 patients in 10 clinics in Sweden and Italy. Evidence is growing that the test battery is useful, reliable and valid for assessment of symptoms during advanced Parkinson’s disease.

Infusion of a levodopa/carbidopa gel into the small intestine has been shown to reduce variation in plasma drug levels and improve clinical response in this patient category. A pharmacokinetic-pharmacodynamic model of this intestinal gel infusion was constructed. Possibly this model can assist the process of individualization of dosage for this treatment through in numero simulations. Results from an exploratory data analysis indicate that severity measures during oral levodopa treatment may be factors to consider when deciding candidates for infusion treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 76 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 621
Parkinson’s disease, telemedicine, motor test, tapping, spiral, self-assessment, home-assessment, outcome measure, electronic diary, patient-reported outcome, remote patient monitoring, levodopa, infusion, pharmacokinetic, pharmacodynamic
National Category
Biomedical Laboratory Science/Technology
Research subject
Medical Informatics
urn:nbn:se:uu:diva-132635 (URN)978-91-554-7947-3 (ISBN)
Public defence
2010-12-18, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00 (Swedish)
Available from: 2010-11-26 Created: 2010-10-23 Last updated: 2011-01-13Bibliographically approved

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Westin, JerkerNyholm, DagKarlsson, Mats
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